occupational-asthma

BIRKH~USERI
Progress in Inflammation Research
Series Editor
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Director of Science
MediMlijeko d.o.o.
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G. Z. Feuerstein (Wyeth Research, Collegeville, PA, USA)
M. Pairet (Boehringer Ingelheim Pharma KG, Biberach a. d. Riss, Germany)
W. van Eden (Universiteit Utrecht, Utrecht, The Netherlands)
Forthcoming titles:
Inflammatory Cardiomyopathy (DCMi) – Pathogenesis and Therapy, H.-P. Schultheiß,
M. Noutsias (Editors), 2010
Endothelial Dysfunction and Inflammation, A. Karsan, S. Dauphinee (Editors), 2010
Muscle, Fat and Inflammation: Sustaining a Healthy Body Composition, S.A. Stimpson,
B. Han, A.N. Billin (Editors), 2011
The Inflammasomes, I. Couillin, V. Petrilli, F. Martinon (Editors), 2011
(Already published titles see last page.)
Occupational Asthma
Torben Sigsgaard
Dick Heederik
Editors
Birkhäuser
Editors
Torben Sigsgaard
School of Public Health
Dept. of Environmental and Occupational Medicine
Aarhus University
Bartholin Allé 2
8000 Århus C
Denmark
Dick Heederik
Institute for Risk Assessment Sciences
Division of Environmental and Occupational Health
Utrecht University
Yalelaan 2
3508 TD Utrecht
Netherlands
Library of Congress Control Number: 2009943448
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Contents
List of contributors
.................................................................
vii
..............................................................................
xi
Jean-Luc Malo and Anthony Newman-Taylor
The history of research on asthma in the workplace – development,
victories and perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1
Dick Heederik and Torben Sigsgaard
Epidemiology and risk factors of occupational respiratory asthma
and occupational sensitization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
17
Hayley L. Jeal, Meinir G. Jones and Paul Cullinan
Epidemiology of laboratory animal allergy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
33
Kjell Torén and Paul D. Blanc
Population-attributable fraction for occupation and asthma . . . . . . . . . . . . . . . . . . . . .
57
André Cartier
Definition and diagnosis of occupational asthma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
71
Paul K. Henneberger and Carrie A. Redlich
Work-exacerbated asthma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
89
Preface
Dennis Nowak
Natural history and prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101
Xaver Baur
Mechanisms of allergic occupational asthma
.....................................
111
Vanessa De Vooght, Valérie Hox, Benoit Nemery
and Jeroen A.J. Vanoirbeek
Mechanisms of occupational asthma caused by low molecular weight
(LMW) chemicals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
Dalip J.S. Sirinathsinghji and Ray G. Hill
Contents
Torben Sigsgaard, Øyvind Omland and Peter S. Thorne
Asthma-like diseases in agriculture. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163
Dick Heederik and Gert Doekes
Allergen and irritant exposure and exposure-response relationships . . . . . . . . . . . . . 185
Francine Kauffmann, Francesc Castro-Giner, Lidwien A.M. Smit,
Rachel Nadif and Manolis Kogevinas
Gene-environment interactions in occupational asthma . . . . . . . . . . . . . . . . . . . . . . . . . . 205
Denyse Gautrin and Jean-Luc Malo
Asthma in apprentice workers. The birth cohort parallel: using apprentices
as a powerful cohort design for studying occupational asthma . . . . . . . . . . . . . . . . . . 229
Sherwood Burge
Management of an individual worker with occupational asthma . . . . . . . . . . . . . . . . 249
Olivier Vandenplas and Vinciane D’Alpaos
Social consequences and quality of life in work-related asthma
.................
271
Vivi Schlünssen, Evert Meijer and Paul K. Henneberger
Prevention of work-related asthma seen from the workplace and
the public health perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281
Henrik Nordman
Prevention and regulatory aspects of exposure to asthmagens
in the workplace . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 299
Kathleen Kreiss and Dick Heederik
Design, conduct and analysis of surveys on work-related asthma . . . . . . . . . . . . . . . 327
Index
vi
................................................................................
355
List of contributors
Xaver Baur, Ordinariat und Zentralinstitut für Arbeitsmedizin und Maritime
Medizin, Universität Hamburg, Seewartenstrasse 10, 20459 Hamburg, Germany;
e-mail: [email protected]
Paul D. Blanc, Division of Occupational and Environmental Medicine, University of
California San Francisco, San Francisco, California, USA
Sherwood Burge, Heart of England NHS Foundation Trust, Birmingham Heartlands Hospital, Bordesley Green East, Birmingham B9 5SS, UK; e-mail: sherwood.
[email protected]
André Cartier, University of Montreal, Department of Medicine, Hôpital du SacréCoeur de Montréal, 5400 Boul. Gouin Ouest, Montréal, P.Q., Canada, H4J 1C5
Francesc Castro-Giner, Centre for Research in Environmental Epidemiology
(CREAL), Barcelona, Spain; e-mail: [email protected]
Paul Cullinan, Department of Occupational and Environmental Medicine, National
Heart and Lung Institute, Imperial College, 1b Manresa Road, London SW3 6LR,
UK; e-mail: [email protected]
Vinciane D’Alpaos, Service de Pneumologie, Cliniques de Mont-Godinne, Université Catholique de Louvain, B-5530, Yvoir, Belgium; e-mail: vinciane.dalpaos@
uclouvain.be
Vanessa De Vooght, O&N 1, Research Unit for Lung Toxicology (Pneumology),
Herestraat 49 bus 706, 3000 Leuven, Belgium; e-mail: vanessa.devooght@med.
kuleuven.be
Gert Doekes, Division of Environmental Epidemiology, Institute for Risk Assessment Sciences, Utrecht University, PO Box 80178, 3508 TD Utrecht, The Netherlands; e-mail: [email protected]
vii
List of contributors
Denyse Gautrin, Axe de recherche en santé respiratoire, Hôpital du Sacré-Coeur de
Montréal, 5400 Gouin Blvd West, Montreal, Canada H4J 1C5; e-mail: d.gautrin@
umontreal.ca
Dick Heederik, Division of Environmental Epidemiology, Institute for Risk Assessment Sciences, University of Utrecht, PO Box 80178, 3508 TD Utrecht, The Netherlands; e-mail: [email protected]
Paul K. Henneberger, National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, MS H2800, 1095 Willowdale Road , Morgantown, WV 26505, USA; e-mail: [email protected]
Valérie Hox, O&N 1, Research Unit for Lung Toxicology (Pneumology), Herestraat
49 bus 706, 3000 Leuven, Belgium; e-mail: [email protected]
Hayley L. Jeal, Department of Occupational and Environmental Medicine, National
Heart and Lung Institute, Imperial College, 1b Manresa Road, London SW3 6LR,
UK; e-mail: [email protected]
Meinir G. Jones, Department of Occupational and Environmental Medicine,
National Heart and Lung Institute, Imperial College, 1b Manresa Road, London
SW3 6LR, UK; e-mail: [email protected]
Francine Kauffmann, Inserm, U780 – Epidemiology and Biostatistics, Villejuif,
France; e-mail: [email protected]
Manolis Kogevinas, Centre for Research in Environmental Epidemiology (CREAL),
Barcelona, Spain; e-mail: [email protected]
Kathleen Kreiss, National Institute for Occupational Safety and Health, 1095 Willowdale Rd., MS-H 2800, Morgantown, WV, 26505, USA; e-mail: [email protected]
Jean-Luc Malo, Axe de recherche en santé respiratoire, Hôpital du Sacré-Coeur de
Montréal, 5400 Gouin Blvd West, Montreal, Canada H4J 1C5; e-mail: [email protected]
Rachel Nadif, Inserm, U780 – Epidemiology and Biostatistics, Villejuif, France;
e-mail: [email protected]
Evert Meijer, IRAS, Institute for Risk Assessment Sciences, Division Environmental
and Occupational Health, Utrecht University, 3508 TD, Utrecht, Netherlands
viii
List of contributors
Benoit Nemery, O&N 1, Research Unit for Lung Toxicology (Pneumology), Herestraat 49 bus 706, 3000 Leuven, Belgium; e-mail: [email protected]
Anthony Newman-Taylor, Faculty of Medicine, Imperial College, London, UK
Henrik Nordman, Finnish Institute of Occupational Health, Topeliuksenkatu 41
aA, 00250 Helsinki, Finland; e-mail: [email protected]
Dennis Nowak, Institute and Outpatient Clinic for Occupational, Social and Environmental Medicine, Clinical Centre, Ludwig Maximilian University, Ziemssenstr.
1, 80336 München, Germany; e-mail: [email protected]
Øyvind Omland, School of Public Health, Department of Environmental and Occupational Medicine, Aarhus University, Denmark
Carrie A. Redlich , Occupational and Environmental Medicine and Pulmonary &
Critical Care Medicine, Yale University School of Medicine, 135 College Street, 3rd
Floor, New Haven, Connecticut 06510, USA; e-mail: [email protected]
Vivi Schlünssen, School of Public Health, Department of Environmental and Occupational Medicine, Aarhus University, Bartholin Allé 2, 8000 Århus C, Denmark;
e-mail: [email protected]
Torben Sigsgaard, School of Public Health, Department of Environmental and
Occupational Medicine, Aarhus University, Bartholin Allé 2, 8000 Århus C, Denmark; e-mail: [email protected]
Lidwien A.M. Smit, Inserm, U780 – Epidemiology and Biostatistics, Villejuif,
France; e-mail: [email protected]
Peter S. Thorne, Environmental Health Sciences Research Center, University of
Iowa, Iowa City, USA
Kjell Torén, Department of Occupational and Environmental Medicine, Sahlgrenska University Hospital, Box 414, 405 30 Göteborg, Sweden; e-mail: kjell.toren@
amm.gu.se
Olivier Vandenplas, Service de Pneumologie, Cliniques de Mont-Godinne, Université Catholique de Louvain, B-5530, Yvoir, Belgium; e-mail: olivier.vandenplas@
uclouvain.be
ix
List of contributors
Jeroen A.J. Vanoirbeek, O&N 1, Research Unit for Lung Toxicology (Pneumology),
Herestraat 49 bus 706, 3000 Leuven, Belgium; e-mail: jeroen.vanoirbeek@med.
kuleuven.be
x
Preface
This issue of “Progress in Inflammatory Research” is dedicated to the different
aspects of Occupational Asthma from the natural history and risk factors to the
preventive strategies and management of the disease.
Now that heavy industry in the Western world has been regulated and reduced
in size, mainly during the last part of the 20th Century, occupational asthma (OA)
has become one of the leading causes of occupational respiratory diseases [1]. From
meta-analyses and systematic reviews, it has been estimated that the attributable
fraction for occupational exposures for the burden of asthma is approximately 15%.
Considering the increasing background prevalence of child- and adult-onset asthma
in the Western world, this is a substantial proportion of the disease spectrum.
One of the challenges of modern research into OA is the possibility of characterizing different phenotypes of asthma. In a recent editorial in the Lancet it was
pointed out that the time has come to accept that asthma is not one entity, but a
construct with different underlying phenotypes [2]. Two phenotypes in particular
have been discussed in the literature in recent years, but more are likely to exist.
These two phenotypes are the allergic and the irritative phenotype, caused by IgEmediated sensitizers and irritants, respectively. The occupational setting offers a
great opportunity to study different asthma phenotypes because high concentrations
of single compounds occur, and therefore the risk for developing asthma is high.
Traditionally OA has been divided into two entities, one immunologically and the
other irritant induced, the latter being characterized by increased bronchial hyperresponsiveness. The immunological type of OA is divided into the IgE-mediated form
and the non-IgE-mediated form. A third entity is emerging from occupations with
exposure to organic dust, and is characterized by neutrophil influx to the airways
and asthma symptoms without IgE-mediated sensitization.
This is a theme in several of the chapters, and it will be an issue for research, not
only in OA but in asthma research in general for the decades to come. Related to
asthma phenotypes is the distinction between asthma, asthma-like symptoms and
chronic obstructive pulmonary disease (COPD). This is especially an issue in the
farm environment, where different types of inflammatory diseases of the airways
xi
Dalip J.S. Sirinathsinghji and Ray G. Hill
Preface
occur in parallel. Here it is quite difficult to distinguish between the different phenotypes, which is also true for other industrial settings with organic dust exposure. The
newer studies in this area clearly point towards a distinction between the wheezy
and the allergic phenotypes. The wheezy phenotype increases, whereas the allergic
phenotype decreases, with increasing organic dust exposure [3, 4].
The prevalences of atopy and asthma have reached new levels in the general
population of the industrialized world. This challenges the prevention of OA. As
these birth cohorts, more of whom are atopic than ever in the past, enter the labor
market, an increased pressure is put on the employers to create an occupational
environment that can accommodate more susceptible people than previously. Paradoxically, people susceptible for developing asthma will be exposed longer to lower
concentrations of pollutants than ever in the post-industrial era. The reason is that,
earlier, the exposure levels encountered would cause immediate problems in the susceptible people, forcing them to leave the work within a short period of time; this is
no longer the case with the improvements seen in modern work environments.
Sensitization has generally been considered not to be associated to exposure
in a classical dose-response-like manner. The latest results from studies with good
exposure assessment and quantitative analyses of sensitization have clearly shown
that this was a misconception since dose-response associations have been seen for
atopics as well as for non-atopics, sparking the discussion of primary prevention of
asthma by preventing sensitization in the workforce [5].
Individual susceptibility will become a more important area of research in the
coming years. A driving force for this research is the technological development in
the field of genomics and application of these techniques in epidemiological studies.
Genetic studies involving gene environment interactions in occupational settings are
a promising path, which will hopefully lead to more insight into the basic mechanisms driving responses to environmental exposures. A whole section of this issue is
related to the semi-experimental studies of apprentice workers entering the working
environment, and their unique findings of the initial sensitization and subsequent
symptoms in bakers. However, the findings from some of these studies do not seem
to directly convey the allergic march deducted from cross-sectional studies [6], and
the symptoms experienced during apprenticeship diminishes after ceasing exposure
[7], meaning that future studies will have to focus on the whole population of workers exposed to high-molecular-weight allergens and not only the fraction of workers
with a specific sensitization towards an allergen.
So far only a few studies have been able to find a relationship between specific
polymorphisms and OA, e.g., CD14 and wheezing in those exposed to organic
dust, and A-1-antitrypsin and bronchial hyperresponsiveness in farming students
[8]. Likewise isocyanate-exposed workers have shown differences in susceptibility
according to Balboni et al. [9]. Not all studies on susceptibility will involve genetic
characterization. Other approaches to characterize different phenotypes may also
find an application. A recent example is separation of populations into low and
xii
Preface
high responders to endotoxin on the basis of whole blood assays (WBA) [10]. In
this study a clear exposure-response relationship was found between endotoxin
exposure and wheezing only in high responders. These observations can be brought
to the next level by investigating, in a WBA assay, the genes that make a person a
high or a low responder. Novel biomedical technology will open avenues for new
research, but will without doubt also raise ethical questions, especially in the work
environment.
January 2010
Torben Sigsgaard
Dick Heederik
References
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Sigsgaard T, Nowak D, Annesi-Maesano I, Nemery B, Toren K, Viegi G, Radon K,
Burge PS, Heederik D (2010) ERS Position paper on: Work related respiratory diseases
in the EU. Eur Respir J 35: 234–238
(2006) A plea to abandon asthma as a disease concept. Lancet 368: 705
Eduard W, Douwes J, Omenaas E, Heederik D (2004) Do farming exposures cause
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381–386
Smit LA, Heederik D, Doekes G, Blom C, van Zweden I, Wouters IM (2008) Exposureresponse analysis of allergy and respiratory symptoms in endotoxin-exposed adults. Eur
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Heederik D, Thorne PS, Doekes G (2002) Health-based occupational exposure limits
for high molecular weight sensitizers: how long is the road we must travel? Ann Occup
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Skjold T, Dahl R, Juhl B, Sigsgaard T (2008) The incidence of respiratory symptoms and
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Gautrin D, Ghezzo H, Infante-Rivard C, Magnan M, L’Archeveque J, Suarthana E,
Malo JL (2008) Long-term outcomes in a prospective cohort of apprentices exposed to
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Sigsgaard T, Brandslund I, Omland O,.Hjort C, Lund ED, Pedersen OF, Miller MR
(2000) S and Z alpha1-antitrypsin alleles are risk factors for bronchial hyperresponsiveness in young farmers: an example of gene/environment interaction. Eur Respir J 16:
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Balboni A, Baricordi OR, Fabbri LM, Gandini E, Ciaccia A, Mapp CE (1996) Association between toluene diisocyanate-induced asthma and DQB1 markers: a possible role
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795–802
xiii
The history of research on asthma in the workplace –
Development, victories and perspectives
Jean-Luc Malo1 and Anthony Newman-Taylor 2
1
The Department of Chest Medicine, Hôpital du Sacré-Cœur de Montréal, 5400 West Gouin
Bld, Montréal, Canada H4J 1C5
2
Faculty of Medicine, Imperial College, London, UK
Abstract
Here we review the historical landmarks of occupational asthma (OA). Although there has been
suspicion for long that proteins can cause allergic sensitisation and OA, it is only in the last century
that evidence that chemicals can cause OA has been published. Acute irritation of the bronchi has
also been incriminated in the genesis of OA. Although an IgE-mediated process has been clearly
identified in OA caused by proteinaceous material, the mechanism of OA remains unknown for
chemicals. Population-based studies, examination of population data bank, sentinel-based studies and prospective interventions in high-risk workplaces have greatly improved our estimates of
the frequency of the condition and helped to identify risk factors. Although diagnostic means are
more diversified, they are still not used sufficiently. However, characterisation of the occupational
environment has become more accurate, and scales for assessing impairment/disability are now
available. Estimates of the proportion of asthma cases that can be ascertained as OA are now
proposed. In a more general way, OA has been proposed as a model of the onset and persistence
of asthma in humans.
Introduction
According to its etymological meaning, asthma refers to a “shallow breathing” as
initially proposed by Homer in the 15th song of the Iliad (850 BC), which describes
the “terrible suffocation” of Hector lying in the plain. Early literature on asthma
has distinguished intrinsic from extrinsic causal factors. The arabic physician Razes
(Abu Bakr Mohammed Ibn Zakaria Al-Razi) (864–930) was the first to identify allergic asthma followed by his colleague Maimonides (Abu Imran Musa Ben
Maimun Ibn Abd Allah) (1138–1204), Saladin’s physician, who, in the first treatise
on asthma “Maqalah fi Al-Rabw”, comments on the influence of heredity, the wintry exacerbations of asthma and the influence of foods, hygiene and emotion. These
extrinsic factors were also reported in Sir John Floyer’s (1649–1734) A Treatise of
the Asthma, in which the author who suffered from asthma reports the improvement due to breathing the fresh air in Oxford. The development of immunology
Occupational Asthma, edited by Torben Sigsgaard and Dick Heederik
© 2010 Birkhäuser / Springer Basel
1
Jean-Luc Malo and Anthony Newman-Taylor
and allergy in the beginning of the 20th century allowed identification of the factors
related to the intrinsic and extrinsic components and to a formal proposal of classification by the American physician Rackeman in 1947.
Although there had been suspicions that the workplace could cause or increase
the severity of asthma before, according to Pepys and Bernstein [1] the Scandinavian
monk Olaus Magnus was, in 1555, the first to describe the difficult breathing that
could occur in grain handlers and might either represent farmer’s lung or asthma.
In their section on “Diseases of sifters and measurers of grain” [1], Bernardino
Ramazzini, the father of occupational medicine, was also reported to have described
the difficult breathing of these workers but his description could also correspond
to farmers’ lung and not necessarily to asthma. In the 19th century, authors such
as Thackrah in England and Patissier in France described the occurrence of what
could be interpreted as chronic bronchitis in malsters, coffee roasters, hatters, hairdressers and as byssinosis in flax mill workers. Castor beans, various gums (acacia,
tragacanth), metal salts and anhydrides were the first occupational sensitising agents
described as formerly causing asthma in reports made early in the 20th century [1].
Interestingly, the agents originally incriminated included both high- and low-molecular-weight agents, in particular isocyanates, a still important cause of occupational
asthma (OA) [2]. The development by Pepys, considered by many to be the father of
OA, of an experimental method of simulated exposure to agents suspected to cause
OA [3] enabled the identification of several causative agents, the description of the
temporal patterns of asthmatic reactions and the inhibitory effect of drugs, such as
sodium cromoglycate and inhaled steroids, on these reactions.
From occupational asthma to asthma in the workplace
Several conditions can be distinguished under the general heading of asthma in the
workplace (Fig. 1). First, the workplace can cause asthma through a known or apparently plausible sensitising process that needs a latency period to induce sensitisation
and cause symptoms; until recently this was the main focus of interest. Since the
early 20th century it had been known that exposure to products with irritant properties could cause pulmonary oedema and bronchial damages [4], the latter being
labelled irritant-induced asthma or reactive airway dysfunction syndrome (acronym:
RADS) by Brooks and co-workers in 1985 [5]. In contrast, study of exacerbations of
asthma at the workplace [6] has been neglected, so that little was known in this field,
although it encompasses socioeconomic consequences that are equivalent to OA [7,
8]. Variants of OA have been described, especially in the aluminium industry, which
reached its peak manufacturing activity in the 20th century. Here potroom workers
were shown to have an excess of respiratory symptoms that included wheezing [9].
Finally, because induced sputum can now be more readily examined, a condition
known as eosinophilic bronchitis has also been identified in recent years [10].
2
The history of research on asthma in the workplace – Development, victories and perspectives
Figure 1.
Different conditions of asthma in the workplace.
Practice guidelines on OA have been issued in the USA [11], Canada [12] and
the UK [13].
Suspicion that chemicals and not only proteins can cause “sensitisation”
The capacity of proteins encountered in the workplace, such as those from castor
bean, gums acacia and tragacanth, to cause asthma as the manifestation of a hypersensitivity response was recognised by the 1930s and 1940s [14–17]. In each case
the development of asthma followed an initial symptom-free period of exposure,
with asthma subsequently provoked by levels of exposure to which the individuals
themselves were previously, and others continued to be, tolerant, fulfilling the clinical criteria of an acquired hypersensitivity response.
Reports of asthma with similar characteristics caused by low-molecular-weight
chemicals encountered at work, such as phthalic anhydride [18] and complex platinum salts [19], followed shortly after. Both of these reports provided evidence for an
associated immediate skin test response, implying the presence of reaginic antibody.
3
Jean-Luc Malo and Anthony Newman-Taylor
Further understanding of the nature and underlying mechanisms of these allergic
reactions followed the development of controlled inhalation testing and the discovery of IgE. Inhalation tests demonstrated that similar patterns of immediate, late,
dual and nocturnal reactions were provoked by inhalation of proteins encountered
both in the general environment (e.g. house dust mite) and at work (enzymes) and
by inhalation of low-molecular-weight chemicals [20, 21].
The discovery in the late 1960s of IgE antibodies as the mediators of reaginic or
allergic activity by Ishizaka et al. [22] and Johannson [23] led to the understanding of the underlying immunological mechanisms of allergic asthma. It is caused
not only by common environmental allergens (e.g. grass pollen, house dust mite)
but also by agents inhaled at work, both proteins and some low-molecular-weight
chemicals. Specific IgE antibodies were shown to be present to many of the important protein causes of OA, including enzymes [24], flour [25], as well as rat and
mouse urine proteins [26]. Specific IgE was also identified to low-molecular-weight
chemicals such as acid anhydrides [27, 28] and reactive dyes [29] that were conjugated to human serum albumin. However, no evidence for specific IgE antibody has
been reproducibly found in cases of asthma caused by the majority of low-molecular-weight chemicals, such as plicatic acid found in Western red cedar [30] and
isocyanates [31, 32]. Although the complex platinum salt ammonium hexachloroplatinate, an essential intermediate in platinum refining, elicits immediate skin prick
test responses in the majority of OA cases caused by this salt, no specific IgE has yet
been reproducibly found in the sera of these cases. The mechanism of asthma caused
by low-molecular-weight chemicals that fulfils the clinical criteria of a hypersensitivity reaction, but where no specific IgE antibody has been reliably found, remains
unclear. It remains possible that the appropriate hapten protein conjugate has not
been used for specific IgE testing. However, the absence of mRNA for the IgE chain
in Th2 lymphocytes from the airways of patients with isocyanate-induced asthma
following an inhalation test asthmatic response, argues against this, at least in cases
of isocyanate-induced asthma without specific IgE in their sera [32].
Assessment of frequency
Most of the early frequency studies of OA were cross-sectional in design and investigated epidemics of work-related asthma in specific industries where cases had been
identified. The potential pitfall of this approach is the healthy survivor bias [33].
More recently, frequency estimates have been obtained by consultation of suitable
registries, either from general population data, especially in Scandinavia [34], or
from medicolegal statistics, with interest in those available in countries where objective means are routinely applied [35]. Sentinel-based projects have been initiated in
several countries and have been fruitful particularly in the USA [36] and the UK
[37]. Prospective studies have been more recently carried out in apprentices in high-
4
The history of research on asthma in the workplace – Development, victories and perspectives
risk fields, so as to document the natural history of the condition [38, 39]. Finally,
large population-based studies like the European Respiratory Health Survey have
included key elements that explore the work-relatedness of symptoms with some
objective testing [40]. There are current attempts to document the frequency of OA
in developing countries where data are still scarce [41].
Occupational asthma as a model for environmental asthma
Asthma caused by allergy to agents inhaled at work has several advantages for
investigation over asthma caused by allergy to environmental allergens, for which
it has been considered a model. These include: a well-defined population at risk; a
well-defined phenotype (both clinical and, for several of its causes, immunological);
maximum risk of developing disease within a relatively short period from onset of
exposure and, with the development of inhibition immunoassays for specific allergens, the opportunity for well-characterised exposure.
A number of studies have exploited these advantages to investigate, in welldefined workforce cohorts, the determinants of allergy and asthma triggered by
several of the different causes of OA, including enzymes used in detergents [42],
Western red cedar [43], rat and mouse urine proteins [44], flour and -amylase [45]
and acid anhydrides [46]. The strength of some of these studies has been in the
follow-up of a proportion of new employees not previously exposed to the relevant
allergen or low-molecular-weight chemical, which helps to overcome the problems
of survivor bias inherent in cross-sectional surveys, and the ability to relate disease
incidence to level of exposure estimated quantitatively by objective measurement
of aeroallergen [47–49]. The use of an entirely prospective model has been particularly fruitful in examining apprentices before they enter a training program [39, 50]
because this represents an experimental situation in which subjects can be examined before, during and even after stopping exposure, so that the determinants for
sensitisation and asthma can be assessed first before any exposure and then before
starting to work [51].
Exposure is a more important determinant than personal and genetic factors
Several studies have consistently demonstrated the importance of the level of exposure to airborne allergen (enzyme, flour, A-amylase, detergent enzyme, acid anhydride, Western red cedar) as the major determinant of risk of developing specific
IgE allergy and/or asthma. Factors such as atopy and cigarette smoking previously
identified as risk factors for some agents (e.g. platinum salts) were found to be of
lesser importance than intensity of exposure. The importance of exposure intensity
as a determinant of OA and of its reduction in reducing disease incidence is well
5
Jean-Luc Malo and Anthony Newman-Taylor
demonstrated by examining the history of asthma caused by occupational exposures
to enzymes in the detergent industry.
Flindt first reported in 1969 [52] that the powdered proteolytic enzyme Alcalase,
derived from Bacillus subtilis, introduced in 1967 in detergent manufacture could
cause allergic reactions, including asthma, in exposed workers. In an accompanying
article in the Lancet, Pepys and colleagues [24] described the results of inhalation
tests with enzyme extracts in affected workers, which provoked immediate and dual
asthmatic reactions, associated with immediate skin prick test responses and specific
IgE to the protease in their sera, providing strong evidence that allergy to protease
was the cause of their asthma.
By 1970, 80% of soap detergents sold in USA contained enzymes. Cross-sectional studies of factory workforces reported high rates of respiratory symptoms and skin
test responses to proteolytic enzymes. In a survey of a UK workforce, Newhouse and
colleagues [53] reported allergic symptoms in 47% of the workforce with an association between a skin test response to enzymes and both allergic symptoms and atopy.
The findings of these studies stimulated important advances, in particular the substitution of powdered enzymes by enzymes encapsulated in granules. This, together
with major engineering improvements, led to a marked reduction in the levels of
airborne enzyme in the workplace [54]. The effectiveness of these interventions
in reducing the incidence of asthma and sensitisation was investigated in a 7-year
follow up of employees of the enzyme detergents-manufacturing factory where
the original cases reported by Flindt had worked [52]. The authors examined the
attack rate before and after the introduction of enzyme granulation and improved
engineering controls. They found that skin test reactions primarily occurred in the
first 2 years of exposure and their incidence was greater in those with higher levels
of exposure and among atopics at each level of exposure. Dust concentration fell by
more than threefold. In parallel with this, the incidence of skin prick test responses
to enzymes and the number of cases transferred from enzyme areas following the
development of respiratory symptoms also fell. Whereas 41% of workers employed
in 1968/69 developed immediate skin prick test reactions to enzymes, of those
employed between 1971 and 1973, 11% developed skin test reactions. Similarly, the
number of cases transferred out of the enzyme area with respiratory symptoms fell
from 50 between 1968 and 1971 to 1 in each year in 1972–1974 [54]. More recent
studies have shown that, while the prevalence of sensitisation to enzymes in the
detergent industry can be high, in general the incidence and prevalence of asthma
has remained low. This, however, was not the case in detergent-producing factory
in NW England, which, despite only using granulated enzymes, was found to have
a high prevalence of allergic disease (both rhinitis and asthma) [55]. Of a factory
population of 350, 19% had work-related nasal symptoms and 16% work-related
asthmatic symptoms together with evidence of specific IgE to protease or amylase
or both. The prevalence of disease showed a clear relationship with estimated levels
of airborne enzyme. The reasons for this high prevalence of allergic disease (compa-
6
The history of research on asthma in the workplace – Development, victories and perspectives
rable to the reported frequencies in the late 1960s/early 1970s) are not clear, but no
other recent studies have reported comparable levels of disease.
The impact of these and other similar studies for disease prevention has stimulated a fundamental shift in focus from the identification and exclusion of a “susceptible” minority of the potential workforce by pre-employment screening, to measures
designed to reduce the levels of exposure to the specific agents in the place of work.
Recent studies of genetic influences on the development of specific IgE and OA have
shown interesting though inconsistent (the number of individuals is generally small)
associations with various HLA phenotypes, some having an enhancing and others
a protective effect [56]. The interesting and potentially important implication of
these observations, if generalisable, is that the more disease incidence is reduced by
controlling levels of exposure, the more important genetic susceptibility will become
as a determinant of sensitisation and asthma.
Diagnostic means
Originally, the diagnosis of OA was mainly based on the clinical history. The
description of OA due to isocyanates, the leading cause of OA, used this approach
[2]. Clinical questionnaires generally represent sensitive but not specific tools for
making a diagnosis of OA [57]. Skin testing to document possible IgE-mediated
sensitisation and spirometry were subsequently used, followed by evaluation of nonspecific bronchial responsiveness, for periods at work and away from work. Pepys
was the first to experimentally document the occurrence of asthmatic reactions on
laboratory exposure to occupational agents [58]. At-work and off-work monitoring of peak expiratory flow rates was subsequently suggested [59], along with the
monitoring of non-OA subjects [60]. Other non-invasive means to document airway
inflammation, a key element included in recent definitions of asthma [61], have
been added to the diagnostic arsenal [62], while attempts to improve the methodology of laboratory challenges have been carried out [63].
Persistence of disease after removal from exposure
For a long time it was naïvely thought that workers with OA would be cured after
removal from exposure. Chan-Yeung and co-workers [64] were the first to show
that asthma generally persists in workers with OA that had been caused by Western
red cedar who were no longer at work. Numerous studies carried out in different populations affected with OA initiated by various agents have subsequently
confirmed this original contribution that has enlightened our understanding of the
natural history of asthma. OA indeed offers a unique opportunity because workers
can be removed from the agent that causes OA, whereas this is not generally feasible
7
Jean-Luc Malo and Anthony Newman-Taylor
for allergic asthma due to ubiquitous allergens. Most often, after cessation of exposure to an agent causing OA, the persistence of asthma is reflected by long-lasting
bronchial hyperresponsiveness that improves at a faster rate in the first 2 years after
removal from exposure than later on [65]. Even when workers are apparently cured
(this occurs in approximately 25% of cases), it has been recently shown that some
airway inflammation and remodelling can persist [66].
Impairment and disability
Whereas means and scales for assessing pneumoconiosis had been developed, these
tools could not be applied in the case of asthma, a disease characterised by variable
airway obstruction. Criteria based on need for medication to control asthma, as
well as levels of airway obstruction and hyperresponsiveness, were proposed by the
American Thoracic Society in 1993 [67] and endorsed more recently by the American Medical Association [68]. Quality of life and general psychological questionnaires can be used to assess disability [69].
Can we prevent the disease and modify its outcome?
The implication of the cohort studies undertaken in the 1990s is that the incidence
of OA could most effectively be diminished by reducing the level of exposure to its
specific causes in the workplace. However, while the inference is clear, evidence for
the effectiveness of interventions designed to reduce disease incidence can only be
provided by well-designed evaluative studies. Studies evaluating the effectiveness of
interventions to reduce exposure levels on disease incidence have now been reported
for a number of the important causes of OA, including enzymes in the detergent
industry, latex in healthcare workers, laboratory animal proteins in a pharmaceutical company and isocyanates in Ontario, Canada. Each of these studies has provided
evidence of a reduction in disease incidence following the intervention. Two studies,
one of isocyanate-exposed workers [70], the other of healthcare workers exposed to
latex proteins [71], both from Ontario, are particularly instructive. In each case the
environmental intervention (regulated reduction in isocyanate levels and substitution of non-powdered low-protein latex gloves for powdered high-protein gloves)
was accompanied by occupational health measures designed to identify cases at an
early stage. In both cases, the institution of occupational health surveillance initially
increased the number of identified cases followed by a fall in the number of cases.
Several studies of the outcome of OA have reported a poor prognosis for OA,
with the majority of cases having continuing symptoms and evidence of airway
hyper-responsiveness 3–5 years after avoidance of exposure. The most consistent
factor associated with a poor outcome has been the duration of symptomatic expo-
8
The history of research on asthma in the workplace – Development, victories and perspectives
sure, i.e. the longer a case of symptomatic OA remains exposed to its cause, the less
likely recovery with avoidance of exposure becomes [35]. These findings emphasise
the need for early recognition of sensitisation and disease and removal of workers
from exposure.
Irritant-induced asthma and reactive airways disease syndrome
This condition, which is rarer than OA with its latency period, has received greater
publicity as a result of inhalational accidents that affected the civil population in
Bhopal [72] and firemen at the site of the World Trade Center [73]. This condition differs from OA, which has a latency period, in that cough is more frequent
than wheeze, airway obstruction is less reversible [74] and the degree of bronchial
responsiveness to methacholine does not reflect the severity of the clinical status.
Occupational rhinitis
Patients with asthma very often have upper airway symptoms, which has led
recently to the proposal of the united airway concept. Better treatment of rhinitis
improves asthma and vice versa. The existence of occupational rhinoconjunctivitis
has been known for years but its investigation and impact have been neglected.
Workers with OA often present rhinoconjunctivitis symptoms, especially in the case
of sensitisation to high-molecular-weight agents. Occupational rhinoconjunctivitis
is commoner than OA [75]. Objective means, such as rhinometry and nasal lavages,
to confirm this condition are being developed [76].
Perspectives
Asthma in the workplace is a condition that has been recognised for centuries,
although more so in the 20th century. Recognition of its importance as a public
health problem and clinical entity can be dated to the outbreaks of allergy and
asthma that occurred in various workplaces in the second part of the 20th. These
outbreaks stimulated the application of methods for assessing frequency and risk
factors, the development of safe and reproducible clinical and immunological criteria, and the recognition of the psychosocioeconomic impact.
We have to face several challenges in the forthcoming years:
-
OA represents only a small proportion of asthma in the workplace, the rest being
mostly asthma exacerbated by the workplace. Better characterisation and assessment of this condition is necessary to prevent and manage it.
9
Jean-Luc Malo and Anthony Newman-Taylor
-
-
-
-
-
-
-
The immunological mechanisms of asthma caused by the majority of chemicals
still remains puzzling, which is a surprise given the fantastic impulse of immunology in recent years. Immunologists have neglected this important field and this
should be corrected.
Refinement of methods to assess the frequency of the disease should be a priority because this represents the ideal means to know whether frequency and the
nature of causal agents vary and whether control efforts are efficient.
The effectiveness of a reduction in the level of aeroallergen concentration in
reducing the incidence of sensitisation and asthma has been demonstrated in
large workplaces. The challenge now is to determine the means to effect this
more widely in locations, such as small bakeries and body repair shops, that are
less amenable to effective intervention than large factories.
OA should be more widely recognised as a valuable model of adult-onset asthma
in particular in examining the complex relationship between genes and the environment.
Considering the existence of various efficient diagnostic means, it is hard to
believe that in developed countries these are seldom applied. General physicians
do not routinely ask questions about occupations and readily prefer to mask
inflammation by prescribing potent steroid inhalers. This results in delays in
diagnosis and maintenance of exposure of the worker with the long-term negative consequences. We have to make general physicians aware of asthma in the
workplace, identify accredited referral centres and promote early referrals.
The medicolegal management of cases is inappropriate even in developed countries. Readaptation programs with retraining and psychosocial interventions
should be preferred to allocation of a lump sum. Scales to assess impairment
have been proposed but tools to evaluate disability have to be further validated
and used.
The characteristics that differentiate irritant-induced asthma from OA with its
latency period should be further identified.
Occupational rhinitis is frequently associated with OA but this condition, which
is even commoner than OA, has not been studied to the same extent. A “united
airways” approach should be explored.
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15
Epidemiology and risk factors of occupational respiratory
asthma and occupational sensitization
Dick Heederik1 and Torben Sigsgaard 2
1
Division of Environmental Epidemiology, Institute for Risk Assessment Sciences,
Utrecht University, The Netherlands
2
Department Environmental and Occupational Medicine, School of Public Health,
Aarhus University, Aarhus, Denmark
Abstract
Information on the occurrence of occupational asthma comes from different sources; disease registries, general population studies and workforce-based studies. Each source has its strengths and
weaknesses. For multi-causal diseases such as asthma, reliable information from well-designed
epidemiological studies is to be preferred. However, a complication is that occupational asthma is
not directly measured (diagnosed) in general population studies and an attributable risk is usually
calculated on the basis of crude information about exposure. The exposure information is usually
derived from questionnaire responses to questions on exposure to gases, fumes or dusts, or is based
on so-called ‘job exposure matrices’. Disease registry data, from occupational disease registries,
allows direct estimation of the occurrence of occupational asthma. However, the information is
often incomplete or difficult to interpret because of diagnostic criteria which vary and can also be
dependent on compensation and insurance criteria, more related to severity of disease rather than
to occurrence of disease. As a result, registries may give only crude estimates of the occurrence of
disease, but at the same time allow evaluation of trends over time. Workforce-based studies have
given most information about determinants of work-related asthma and allergy. An important
determinant of asthma and allergy is the exposure intensity and for high-molecular-weight sensitizers atopy clearly modifies the risk. It is expected that improved phenotypical characterization of
occupational asthma together with genotyping and detailed exposure assessment will give more
insight in the occurrence and determinants of disease and prognosis.
General introduction
In Western countries there has been a clear shift observable over the last few decades
from pneumoconiosis and cancer due to mineral dust exposures (asbestos and silica)
to work-related obstructive diseases such as occupational asthma (OA) and chronic
obstructive pulmonary disease (COPD) [1]. In most Western countries, OA is now
the most frequently occurring occupational disease. Information about the occurrence of occupational respiratory diseases and their contribution to morbidity and
mortality in the general population comes from different sources of varying quality.
Occupational Asthma, edited by Torben Sigsgaard and Dick Heederik
© 2010 Birkhäuser / Springer Basel
17
Dick Heederik and Torben Sigsgaard
Data from these different sources are not always easily comparable since the quality
of the information, and the aims for which they were gathered, differ. Nevertheless,
an attempt is made in this chapter to give insight into the associations between
occupational exposures to occurrence of OA. Information on determinants of OA
mainly comes from workforce-based studies, and these determinants are also briefly
discussed.
Occupational asthma in an epidemiological context
OA is usually defined as a disease characterized by variable airway airflow limitation and/or airway hyperresponsiveness due to causes and conditions attributable
to a particular workplace environment and not to stimuli encountered outside the
workplace [2]. Usually, OA with and without a latency period is distinguished.
Asthma with a latency period includes all forms of asthma for which an immunological mechanism has been identified. In most cases an IgE-mediated allergy
is the underlying mechanism. Causes of immunological asthma are low- and
high-molecular-weight sensitizers of which more than 250 have been identified.
High-molecular-weight sensitizers are usually large proteins of more than 5 kDa
such as enzymes like fungal A-amylase derived from Aspergillus oryzae, or more
heterogeneous natural substances such as latex and cereals like wheat. Most highmolecular-weight sensitizers induce the development of specific IgE antibodies. The
reaction between antibody and allergen leads to an allergic inflammatory response
in the airways. Few population studies exist that focus on the changes shortly after
sensitization, but a small longitudinal study in laboratory animal workers suggests
that bronchial hyperresponsiveness and symptoms develop soon after sensitization,
and accelerated decline in lung function becomes measurable [3].
For many other substances the mechanism by which inflammation develops
is often at least partially unknown. Specific antibodies against isocyanates for
instance have been found in a minority of the sensitized workers, but the role of
these antibodies is not completely clear, and the mechanism does not seems to be
IgE mediated in all isocyanate-sensitized workers [4, 5]. Irritants induce asthma by
non-immunological mechanisms and no latency period is observed in most cases.
An example of OA without a latency period is the reactive airways dysfunction
syndrome (RADS), which develops after exceptionally high concentrations of an
irritant agent. Small work shift changes in lung function, without persistent bronchial hyperresponsiveness and eosinophilia are usually not referred to as OA, but as
OA-like disorders. A typical example of an asthma-like disorder is Monday morning
airway obstruction associated with endotoxin exposure in agricultural workers [6],
although some nowadays may refer to this as non-allergic asthma [7, 8].
There is no consensus on the best way to identify OA in epidemiological studies.
A provocation test with the suspected causal agent is generally accepted as the gold
18
Epidemiology and risk factors of occupational respiratory asthma and occupational sensitization
standard, but this approach cannot be applied in large scale surveys of industrybased studies or the general population. Questionnaires form an important survey
tool and many have modified these questionnaires for their own purposes by adding questions on work relatedness of symptoms [9]. Other relevant tests that can
be applied in surveys are bronchial hyperresponsiveness testing, spirometry, serology and skin prick testing for evaluation of sensitization in case of immunological
asthma. Records of peak expiratory flow (PEF) measurements over longer periods
have been commonly used for establishing a clinical diagnosis. Unfortunately, few
examples can be found of application in epidemiological studies, and the response
rate for repeated PEF testing in population surveys is usually low [10].
Incidence data from monitoring systems
Considerable attention has been given to disease monitoring systems for asthma
across the world since the mid-1990s when it became apparent that OA had
replaced the pneumoconiosis as the leading occupational disease. A major source
of information included disease registries for compensation purposes, since these
also give an impression of the burden on society of OA. Point estimates from
occupational disease registries indicated an incidence between 2 and 15 cases per
100 000 (Tab. 1). Differences are, among other factors, associated with differences
in industrial structure between countries, differences in definition of work-related
(and compensable) asthma, differences in case finding methods, and changes over
time in asthma incidence. Through the voluntary Surveillance of Work Related and
Table 1. Reported occupational asthma incidence by different asthma monitoring programs
and some occupational disease registries.
Reference
Country
Incidence/100 000
Range
[11, 13, 15, 17]
UK
2.0-4.3
1–183 [17]
[12]
USA
2.9
0–17
[14]
Finland
3.6
5–30
[16]
Germany
4.2
[18]
Canada (Quebec)
6.3
[19]
Sweden
8.1-19.1
[20, 21, 23–25]
Finland
8.1
[22]
Canada (Br. Columbia)
9.2
[26]
USA
1–77
5.8–20.4*
*Estimates based on capture-recapture method
19
Dick Heederik and Torben Sigsgaard
Ocupational Respiratory Disease (SWORD) reporting system in the UK, occupational physicians, lung specialists and allergists voluntarily reported 3000–4500
cases of respiratory diseases. More than a quarter of the cases involved OA, which
makes OA the most reported work-related respiratory disease. Diisocyanates,
which are low-molecular-weight sensitizers, and high-molecular-weight allergens
from animals, flour and grain appear the most important sensitizers. In Germany,
only 1500 of the 5600 suspected cases could be confirmed as OA [16]. Of these,
another 400 were rejected because they were not in accordance with additional
clinical or non-medical criteria. In a study from the USA, OA cases reported
through different disease registries in one state were evaluated using the capturerecapture method, a statistical technique that used the overlap between sources of
information to obtain an estimate of the ‘true’ rate [26]. Reports from physicians,
hospital discharge records and worker compensation claims were used, and the
incidence of new onset OA was estimated between 5.8 and 20.4 cases/100 000
individuals per year, clearly higher than the directly observed incidence of 2.7
cases/100 000 individuals per year, but in range with the data from registries in
other countries. Some disease registries have been able to show strong changing
trends in numbers of reported cases reported, like for latex-associated respiratory
allergy in Germany [27]. A strong drop in cases was associated with a targeted
reduction of exposure to powdered high-protein latex gloves. Similarly, in Ontario,
Canada, a program to reduce exposure to diisocyanates and to introduce medical
surveillance was associated with earlier diagnosis and fewer cases in a compensation population [28].
Occurrence in general population studies
General population studies were more often explored as a means to estimate the
population attributable risk for both asthma and COPD since the late-1970s and
mid-1980s [29–46]. This design became popular because it was believed that general population studies were less sensitive to the healthy worker effect. A general
population sample was considered superior compared to a workforce-based population sample from which workers who had developed disease had already left.
General population studies allowed evaluation of associations between job title and
asthma not only for the present but also for previous jobs [47]. This made a more
direct evaluation of the healthy worker effect possible. In addition, introduction of
so-called ‘Job Exposure Matrices’ – expert systems that cross-link job titles with
specific occupational exposures in a qualitative or semi-quantitative way – made
characterization of exposure possible in these studies. A strength of these general
population studies is that exposures have been identified that were outside the classical basic high-risk industries. An example is the identification of cleaning agents
as a cause of OA [48].
20
Epidemiology and risk factors of occupational respiratory asthma and occupational sensitization
The early general population studies made use of self-reported exposure and
some may have been affected to some extent by misclassification of exposure in
the form of recall bias. Most studies were cross-sectional and used prevalence data.
The studies included information on respiratory symptoms associated with asthma,
lung function or bronchial hyperresponsiveness testing, and allowed calculation of
the risk for developing asthma for individuals with a certain exposure. This allowed
the calculation of the contribution of occupational exposures to the prevalence
of asthma, the etiological fraction. Most studies estimate contributions as being
between a few percent and 20%.
An important example is the large prospective one among 6837 participants
from 13 countries who previously took part in the European Community Respiratory Health Survey (1990–1995) [49]. The individuals included did not report
respiratory symptoms or a history of asthma at baseline. Asthma was assessed by
methacholine challenge test and by questionnaire-registered asthma symptoms.
Exposures were defined by high-risk occupations, an asthma-specific job exposure
matrix with additional expert judgment, and through self-report of acute inhalation events. A significant excess asthma risk was seen after exposure to substances
known to cause OA [relative risk (RR), 1.6; 95% CI 1.1–2.3]. Risks were highest
for asthma defined by bronchial hyperreactivity in addition to symptoms (RR, 2.4;
95% CI 1.3–4.6). Asthma risk was increased in participants who reported an acute
symptomatic inhalation event (fire, mixing cleaning products, chemical spill) (RR,
3.3; 95% CI 1.0–11.1). The population-attributable risk for adult asthma due to
occupational exposures ranged from 10% to 25%. This is equivalent to an incidence of new-onset OA of 250–300 cases per million people per year. Although this
study is among the larger general population studies, it shows some specific limitations of general population studies. Risk estimates for specific occupational groups
are sometimes based on small sample sizes, leading to instability in the risk estimates
for specific occupational titles or exposures. Intermediary endpoints such as specific
work-related sensitization have up to now not been included in general population
studies and this makes it difficult to link results to workforce-based studies. A future
challenge for all general population study is adequate exposure assessment. People
move more frequently from job to job and the exposure is more diffusely spread
through the population in modern service economies without large basic industries.
This makes characterization of the exposure on the basis of job title information
more challenging and probably more detailed techniques will be required.
Occurrence of occupational asthma in workforce-based studies
Important information also comes from studies in specific workforces. For instance
studies in bakers suggest sensitization rates of 5–25% for several work-related
allergens [50], which is in most cases accompanied by symptoms. Similar figures
21
Dick Heederik and Torben Sigsgaard
are available for workers exposure to a range of high- and low-molecular-weight
allergens. Typically, workforce-based studies have a cross-sectional or cohort design
and include between 100 and 1000 workers. Given the incidence of OA, these studies are usually too small to directly study the occurrence of clinically relevant OA.
Therefore, asthma is defined on the basis of questionnaire responses and intermediate effects such as sensitization or hyperresponsiveness are considered as endpoints
in the analysis.
The discrepancies in the magnitude of the hazard estimated by different information sources (general population studies, disease registries, and studies in specific occupational groups) is most likely due to differences in (the definition of)
endpoints considered, the diagnosis, and severity of what is considered OA, and
selection out of the workforce. Most evidence on determinants and modifiers of
risk for OA comes from workforce-based studies. Modern workforce-based studies
often involve a quantitative exposure assessment component. Phenotypical evaluation of the workers is often more detailed and specifically chosen for the type of
asthma resulting from the exposure than in general population studies. The information that is generated by this type of study contributes to risk assessment and
prevention.
Exposure
Allergen exposure level is a clear determinant of risk of occupational allergy and
asthma. Exposure-response relationships have been shown for both high- and lowmolecular-weight sensitizers. Some recent studies in specific occupational groups
illustrated the existence of exposure sensitization relationships for some highmolecular-weight sensitizers. In particular, a series of European studies in bakers
and laboratory animal workers shed new light on some aspects of the development
of occupational allergic asthma and rhinitis due to exposure to high-molecularweight sensitizers. A more complete overview can be found elsewhere [51–56]. A
small retrospective cohort study among laboratory animal workers, who underwent
a pre-employment medical examination, indicated that the time until development
of symptoms was dependent on both exposure intensity and atopy [57]. The risk
for developing sensitization and allergy is measurable directly after start of exposure and remains high with ongoing exposure. A follow-up study showed that the
12-year incidence rates of symptoms among workers from laboratories exposed
to rodents were 2.26 (95% CI 1.61–2.91) and 1.32 (95% CI 0.76–1.87) per 100
person-years, respectively. Higher relative risks were seen with increasing hours of
exposure to tasks that involved working with animal cages or with many animals
at one time. The most common symptoms were related to rhinitis rather than to
asthma. Incidence might be reduced by limiting exposure through reducing the number of hours per week of exposure to laboratory animals [58, 59].
22
Epidemiology and risk factors of occupational respiratory asthma and occupational sensitization
Atopy
Atopy is usually defined as either specific IgE against a series of common allergens
or a positive skin prick test response to the same panel of allergens. Usually, tree
pollen, grass pollen, house dust mite, cat and dog allergens are considered common
allergens in occupational studies. Atopy is a strong risk modifier for high-molecularweight sensitization. This is most clearly illustrated by a large pooled European
study in 650 Laboratory Animal Workers [56]. Atopic workers were at higher risk
for having work-related sensitization compared to non-atopic workers. The atopic
workers already had a clearly increased risk at the lowest exposure levels and
there was no evidence of an exposure threshold. For non-atopic workers a steadily
increasing exposure-response relationship was found. Atopy is the most important
risk modifier of work-related sensitization high-molecular-weight sensitizers. There
is no clear evidence that atopy is a modifier of the risk for work-related sensitization
and asthma in case of low-molecular-weight sensitizers.
Atopy was until recently seen as an individual susceptibility factor with presumably a genetic background. However, atopy has no perfect penetration and cannot
only be interpreted as a factor solely determined by individual susceptibility. It
seems also associated with environmental factors. There is increasing evidence that
farm exposures throughout life are protective against atopy, allergic rhinitis, and
atopic asthma [60]. Several studies have observed a strongly decreased prevalence of
allergic sensitization [61–63], hay fever [64, 65], and asthma [8] among adults with
childhood and current farm exposures. According to the hygiene hypothesis, bacterial and viral infections, and environmental exposures to microbial compounds may
protect from the development of allergic disease by influencing immune responses.
Farmers, and children growing up on farms, are exposed to high levels of microbial
pathogens causing zoonoses, and proinflammatory agents such as bacterial endotoxin and fungal B(1 m 3)-glucans. It has been hypothesized that exposure to such
agents may induce a shift from atopic Th2 responses to Th1 responses through
stimulation of the innate immune system and regulatory T cells [66]. Protective
effects of house dust endotoxin on the development of atopy and asthma have been
shown in children [67–69], and more recently, studies among adults have shown
similar inverse relationships between endotoxin exposure and atopic asthma [8],
allergic sensitization [65, 70, 71], and hay fever [64]. Thus, the more recent studies among occupationally exposed populations have shown that, in accordance
with the hygiene hypothesis, effects of early exposures can be long-lasting. However, some of these studies also suggest that immune deviation from Th2 to Th1
responses may take place throughout life, and exposure in adulthood to endotoxin
and other microbial compounds seem been associated with a lower prevalence of
allergy or allergic asthma. Most evidence is still based on cross-sectional studies,
and longitudinal studies are needed to observe reversal of atopic status under the
influence of high microbial exposures directly.
23
Dick Heederik and Torben Sigsgaard
Since endotoxin and other microbial agents are potent proinflammatory agents,
the downside of increased exposure can be an elevated risk of non-allergic or
non-atopic asthma [72–74]. Only a few studies have explicitly reported the Janusfaced nature of endotoxin – a protective effect on atopic disease, paralleled by
an increased risk of non-atopic asthma and non-specific airway hyperresponsiveness – in the same population sample. There also appears to be a clear difference
in susceptibility for endotoxin exposure, measurable at the population level [75]
(Fig. 1).
Figure 1.
Different exposure-response relationships for endotoxin exposure and wheeze for low and
high responders in a whole blood stimulation assay. Low (gray line) and high (black line)
responders defined on their tumor necrosis factor-A (A), interleukin-1B (B), and interleukin-10 responses (C). Exposure expressed in endotoxin units (EU) (with permission from
[75]).
Smoking
One study identified smoking of cigarettes as a risk factor of work-related sensitization for high-molecular-weight sensitizers [76]. Smokers seemed at higher risk to
have work-related sensitization in especially one of the three subsamples than nonsmokers in this cross-sectional study. However, this finding has not been reproduced
in many larger and better controlled studies [55, 56, 77]. Most evidence available at
present for high-molecular-weight sensitizers indicates that smoking is not an effect
modifier for the association between allergen exposure, sensitization and allergic
asthma. Interesting results have recently been published for other sensitizing agents
such as platinum salts. For low-molecular-weight sensitizers, such as platinum salts,
smoking is an effect modifier [78–80]. The incidence of platinum salt sensitization
depended on the solubility of the platinum salt, after correction for smoking habits
at median levels below 0.5 Mg/m3 [79].
24
Epidemiology and risk factors of occupational respiratory asthma and occupational sensitization
Genetic markers
Studies on the role of genetic markers have traditionally been conducted on relatively small samples of OA cases or within industrial cohorts, especially considering
workers with exposure to specific agents such as isocyanates and red cedar wood
dust. The genes associated so far with OA are HLA class II genes, genes involved
in antioxidant protection, A-1-antitrypsin, and genes regulating the native immune
pathways (see for review [81]). Few interactions have been demonstrated as yet but
large-scale genetic studies of asthma that are now underway will likely change the
situation. A first genome-wide association study (GWAS) including large working
populations will be published soon, but yielded little important information on
top of GWAS studies among adult asthmatics not specifically focused on occupational exposures. It is expected that a new generation of studies based on specific
hypotheses (candidate interactions) in combination with improved phenotypical
and environmental characterization will create more useful evidence on gene
environment interactions. There is awareness about the potential use of genetic
information in, for instance, pre-employment testing and asthma surveillance [82].
However, the associations between genetic markers and asthma or sensitization
are based on cross-sectional analyses and usually relatively weak. Prediction of
future occurrence of disease is practically not possible at the moment and present
information indicates that predictions will be imprecise. A study among laboratory
animal workers for instance showed that HLA-DR7 was associated with sensitization [odds ratio (OR), 1.82; CI, 1.12–2.97], respiratory symptoms at work (OR,
2.96; CI, 1.64–5.37) and, most strongly, sensitization with symptoms (OR, 3.81;
CI, 1.90–7.65) [83]. HLA-DR3 was protective against sensitization (OR, 0.55; CI,
0.31–0.97). Atopy defined phenotypically, on the basis of an immunological evaluation, was more strongly associated with work-related sensitization than any of the
phenotypical markers.
Prognosis
A limited number of epidemiological studies focused on the prognosis of OA [84–
88]. The available studies suggest that symptoms can still be present up to 12 years
after exposure cessation [84, 85]. One study describes results from an interview
6 years after diagnosis of a group of 79 individuals with OA [86]. Most had the
impression that symptoms had improved, although 72% still used medication and
33% were still unemployed. Others found indications that symptoms can still worsen after exposure is terminated [24, 89]. Some have argued that exposure reduction
is associated with a poorer prognosis than complete removal from exposure [90].
However, the studies underlying this statement involved a limited number of asthma
cases and were poorly controlled in terms of the exposure [91, 92]. The changes in
25
Dick Heederik and Torben Sigsgaard
exposure were only monitored qualitatively, and it is not known if any exposure
reduction occurred objectively or that the exposure reduction was sufficiently large
to have any effect.
Prevention
Information on exposure-response relationships can be used for risk assessments and
will be the input of standard setting procedures in different countries. For instance,
the American Conference of Governmental Industrial Hygienists and the Dutch
Health Council are among the first to use data on exposure-response relationships
for bio-aerosols, such as wheat allergens, to propose a standard for wheat dust
levels in the air [93, 94]. It is expected that similar standards will be developed for
some other high-molecular-weight sensitizers because the principles for risk assessment for sensitizing agents have recently been described [95]. Standards do exist
for several low-molecular-weight sensitizers, such as toluene diisocyanate (TDI) and
platinum salts, but it not the rule that these standards take into account the risk for
sensitization. In addition, some of these standards were derived several decades ago,
and it is not always certain what the scientific basis was for these standards and if
they truly protect the workers.
Future developments
Over the last few years, new technologies have become available to measure inflammatory markers in nasal and bronchial lavage samples. Less invasive technologies
are expected to become available such as exhaled nitric oxide (eNO) and measurements based on exhaled breath condensate samples or exhaled air. These developments will give more insight into the heterogeneity in phenotypes and will improve
phenotyping in epidemiological studies. Some examples of this development do
already exist, but usually refer to patient data and seldom come from open population studies.
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Epidemiology of laboratory animal allergy
Hayley L. Jeal, Meinir G. Jones and Paul Cullinan
Department of Occupational and Environmental Medicine, National Heart and Lung
Institute, Imperial College, 1b Manresa Road, London SW3 6LR, UK
Abstract
Laboratory animal allergy is common and an important occupational health issue for the research,
pharmaceutical and toxicological sectors. In most settings where there is regular contact with laboratory animals – chiefly small mammals – the prevalence of specific sensitisation is around 15%
and the prevalence of clinical allergy around 10%. These figures probably underestimate the true
risk of disease since epidemiological studies of the disease have been beset by response and survivor
biases. Allergen exposure appears to be the most important modifiable risk factor, but the effects
of such exposure seem to be modified importantly by individual susceptibility. Laboratory animal
research shows no signs of becoming less common, and an increasingly susceptible (atopic) population is likely to be recruited into such work. Future studies should be designed to take into account
the inherent biases of occupational epidemiology, to study in detail the immunological mechanisms
that underlie sensitisation and tolerance, and to identify early biomarkers of each.
Introduction
Human allergy to furred animals has a history, presumably, that is as long as that
of the domestication of wild beasts. With a general increase in atopy it is probably
more common now than it has ever been. Animal allergy in an occupational, laboratory setting on the other hand is a far more recent phenomenon, reflecting the
development of vivisection as a means of studying human biology and responses to
toxins and pharmaceuticals.
Early descriptions of laboratory animal allergy were in case report form only and
are reviewed by Hunskaar and Fosse [1]. An interesting example is given by Sorrell
and Gottesman [2] who in 1957 reported a single case of mouse allergy in a female
research worker after she developed rhinitis at work. She was treated by specific
immunotherapy with an autogenous extract, after which she was able to continue
working with mice for up to 4 h at a time.
In 1961 Rakja identified, on the basis of skin and exposure tests, ten cases of laboratory animal allergy at the Karolinska Hospital in Sweden [3] and suggested that
Occupational Asthma, edited by Torben Sigsgaard and Dick Heederik
© 2010 Birkhäuser / Springer Basel
33
Hayley L. Jeal, Meinir G. Jones and Paul Cullinan
hypersensitivity to laboratory animals was not as uncommon in research laboratory
workers as might previously have been thought. It was not until the 1970s, however,
that proper epidemiological studies of laboratory animal workers were carried out
and a better idea of the scale of the occupational problem was determined. Over the
subsequent 35 years laboratory animal allergy has been the subject of extensive epidemiological study and is now universally recognised as an important occupational
health issue. With the possible exception of baker’s asthma, it is the best understood
of all the occupational respiratory allergies.
Causes, species and allergens
The contemporary use of animals for research purposes is dominated by the pharmaceutical, toxicological and academic sectors. In 2007, for example, just over
3.2 million scientific procedures were carried out on animals in the United Kingdom; 83% included rodents. The total number was a 6% rise over the previous
year, due mainly to an increase in the use of genetically modified mice in scientific
experiments.
A bewildering variety of animal species are used in laboratory-based research
(Tab. 1). Most procedures use mammalian species and, as the figures above suggest,
most of these now involve mice because of the relative ease of genetic manipulation
in that species. Other commonly used mammals include rats, guinea pigs, hamsters
and ferrets, cats and dogs, pigs, sheep and goats. Non-human primate research is far
less common; interestingly human allergy to other primates appears to be very rare.
Commonly used non-mammalian species include insects, amphibians and fish;
allergic responses to the last two of these appear to be extremely rare. A wide variety
of species of insects have been identified as causing occupational allergy: fruit flies,
cockroaches, locusts, grasshoppers, bumblebees, mites, spiders and chironomid
midges. Birds are occasionally used in research, chiefly in behavioural studies.
Table 1 lists commonly used species and their associated allergens. The majority of the major mammalian allergens belong to a family of proteins known as
lipocalins [4]. The sequence identity of lipocalin allergens often falls below 20% but
they have a similar three-dimensional structure and contain between one and three
structurally conserved regions [5]. Lipocalins also share biological functions that
predominantly relate to the transport of small hydrophobic ligands such as vitamins
and pheromones. Interestingly, lipocalins share a sequence homology with schistosome proteins and it is possible that molecular mimicry may be responsible for the
high rates of sensitisation to lipocalin allergens in the workplace.
Laboratory animal workers may also be exposed to other types of allergen in the
workplace. These include allergens in animal or fish food (such as mealworms or
corn cob), natural rubber latex (gloves), moulds, pollens, enzymes, antibiotics and
several sensitising chemicals
34
Epidemiology of laboratory animal allergy
Table 1. Animal species (and associated allergens) commonly used in laboratory research
Species
Allergens
Mol. mass Source
(kDa)
Mammalian
Mouse (Mus musculus)
Mus m 1 (prealbumin)
Mus m 2
Albumin
19
16
68
Hair, dander, urine
Hair, dander, urine
Serum
Rat (Rattus norvegicus)
Rat n 1 Rat n 2
(A2uglobulin)
Albumin
21
17
67
Hair, dander, urine
Hair, dander, urine
Serum
Guinea pig (Cavia porcellus)
Cav p 1 Cav p 2
20
17
Hair, dander, urine
Hair, dander, urine
Hamster (Cricetus cricetus)
Unknown
-
-
Ferret (Mustela putorius furo)
Unknown
-
-
Rabbit (Oryctolagus cuniculus) Ory c 1
Ory c 2
17
21
Hair, dander, saliva
Hair, dander, urine
Cat (Felis domesticus)
Fel d 1
Fel d 4
Albumin
38
19.7
65–69
Hair, dander, saliva
Saliva
Serum, dander, saliva
Dog (Canis familaris)
Can f 1
Can f 2
Albumin
25
19
67
Pig (Sus domesticus)
Unknown
-
-
Sheep (Ovis aries)
Unknown
-
-
Goat (Capra hircus)
Unknown
-
-
Fruit fly (Drosophila
melanogaster)
Unknown
-
-
Locust (several species)
Unknown
-
-
Cockroach (several species)
Bla g 2
Bla g 4
Bla g 5
Hair, dander, saliva
Hair, dander, saliva
Serum
Other
36
21
23
Faeces, saliva and
body of cockroach
35
Hayley L. Jeal, Meinir G. Jones and Paul Cullinan
Clinical characteristics of laboratory animal allergy
Laboratory animal allergy has clinical characteristics typical of an immediatetype hypersensitivity to a protein aeroallergen. Symptoms develop after a latent
period of exposure that is generally between 3 and 24 months. Upper respiratory
symptoms of rhinitis and itchy eyes are almost universal and may be accompanied
by asthma and by urticarial skin responses to animal scratches or abrasions. In
the early stages of disease there is noticeable improvement when away from the
workplace. With continuing exposure a hypersensitive state tends to develop with
symptoms provoked by increasingly smaller exposures [6] and any improvement
away from work becoming less apparent. Under these conditions standard treatments for asthma and rhinitis are relatively ineffective. Conversely, the avoidance
of exposure to the causative allergen generally results in considerable – or complete
– improvement.
As with its symptomatology, the immunopathology of laboratory animal allergy
is typical of a type 1 allergic response. The development of sensitisation is complex
and involves interaction of antigen-presenting cells and Th2 lymphocytes, which
secrete IL-4, IL-5, IL-9 and IL-13 cytokines leading to an allergic response, with
associated specific IgE response that may be detected by serum assay or skin prick
testing. With appropriate test methods for all relevant allergens the detection of an
IgE response is almost wholly sensitive. Thus, the false-negative rate is very low,
and a negative result to both skin prick testing and serum assay effectively rules out
the diagnosis.
Disease frequency
There are several ways in which the prevalence or incidence of laboratory animal
allergy may be estimated. Each has particular drawbacks but all probably underestimate the true frequency of disease. The reasons for this include:
-
-
36
Specific sensitisation to animal proteins may be clinically unapparent and thus
detectable only through skin prick testing or by the measurement of serumspecific IgE antibodies. Survey methods that do not include such techniques will
lead to an underestimation of the true frequency of sensitisation.
The tools – generally self-completed questionnaires – that are used to determine
the frequency of laboratory animal allergy in clinical or workplace populations may be insensitive; either intrinsically as they may not include all relevant
questions or because participants may be reluctant to disclose full information.
While high sensitivity is desirable in obtaining a true estimate of disease prevalence, specificity is also important, particularly in deriving unbiased estimates of
exposure-response relationships [7].
Epidemiology of laboratory animal allergy
-
-
Epidemiological methods that do not include all or a very high proportion of
the eligible population are likely to suffer from a responder bias. The direction
of this bias in the context of laboratory animal allergy is not known but it is the
experience of the authors that symptomatic workers are less likely to participate
in surveys.
The use of cross-sectional survey to measure the prevalence of laboratory animal
allergy probably incurs a risk of survivor bias, an example of a healthy worker
effect. Employees who have developed laboratory animal allergy may be more
likely than others to seek alternative employment or, within the workplace, to
move to jobs that entail less (or no) exposure to the allergens that incite their
symptoms [8]. The first process (selection out of the workforce) will result in a
cross-sectional population whose disease experience is healthier than is truly the
case; the second (selection within the workplace) may lead to erroneous estimates of exposure-response relationships.
If conducted carefully, cohort studies provide not only a measure of the incidence of
laboratory animal allergy but potentially also an account of any (internal) selection,
and thus an unbiased estimate of exposure-response relationships. In practice they
have rarely if ever been entirely successful in these respects; they are certainly far
less common than cross-sectional designs.
As with the case of potential responder bias, the size of any ‘healthy worker’
effect in the animal laboratory setting is unknown. There are several probable determinants that include the relatively short latency period for the induction of laboratory animal allergy and, once disease has developed, the very brief interval between
exposure and the elicitation of symptoms. Once established and under conditions of
continuing exposure, laboratory animal allergy displays other characteristics of an
immediate-type hypersensitivity, in particular the incitement of symptoms at increasingly low concentrations of allergen exposure. Each of these factors permits an obvious relationship between exposures at work and the manifestations of disease and
together they are likely to have an important influence on employment behaviour.
More individual factors that are likely also to impact on retention within a job or
a workplace include the severity of symptoms – which appears to be variable – and
the attitudes of employers. For the most part, those who employ laboratory animal
workers have a more enlightened view of occupational disease among their employees than is generally the case. Thus, many laboratory animal workers with a specific
occupational allergy are afforded an unusual degree of flexibility in their work.
Cross-sectional surveys
The most common approach to measuring the frequency of laboratory animal
allergy is to estimate its prevalence through the use of a cross-sectional survey of a
37
Hayley L. Jeal, Meinir G. Jones and Paul Cullinan
workforce. Table 2 provides a comprehensive but succinct summary of published
results from 29 such surveys. The numbers of employees included range from 62 to
over 5500; where information is available response rates between 61% and, in some
cases, 100% are reported.
The reported prevalences of ‘allergic symptoms’ vary widely from around 10%
(‘any symptoms’) to over 50%. There is similar if less pronounced variability in
the estimated prevalences of specific sensitisation. Such variation has at least three
sources: true variation reflecting differences in site- or population-specific risk factors; between-study inconsistency in the definition and measurement of ‘allergy’; and
variation in the study populations reflecting, as above, different survival patterns.
Perhaps the most important of these is the second. Very few published crosssectional surveys provide sufficient information on the constitution of their surveyed
population; even the most basic information, such as on the duration of employment, is frequently lacking. Thus, it is generally very difficult to judge to what extent
the reported findings reflect true disease incidence rather than the effects of important survival processes. Even the apparently consistent – and certainly plausible
– observation that upper respiratory symptoms (rhinitis) are more common than
symptoms of asthma may in part be a result of employees with asthma re-locating
at a greater frequency than those with rhinitis alone.
Few cross-sectional surveys have attempted to address this problem. Exceptions
include a study of research workers in the United Kingdom [8] in which analyses
were restricted to those who had not had exposure to laboratory animals prior to
their current employment, and surveys by Hollander et al. [27] and Heederik et al.
[28] in which analysis was confined to employees with less than 4 years exposure
to laboratory animals. Although imperfect, these techniques probably lessen the
impact of any healthy worker effect and may lead to associations that approximate
those observed in cohort studies.
A recent ecological examination of prevalence estimates from 15 cross-sectional
surveys concluded that the prevalence of occupational asthma – but not of occupational rhinitis – among laboratory workers had declined by about 50% between
1976 and 2001 [34]. This decline was not, however, evident in those studies where
workers were exposed to rats, mice, rabbits or guinea pigs. Comparisons such as
these should be viewed cautiously since, as above, studies in this field rarely share
a common methodology. Thus, it is not possible to account for the several biases
inherent in cross-sectional epidemiology, particularly perhaps those that relate to
survival pressures.
Cohort studies
Cohort (‘longitudinal’) studies circumvent many of the difficulties associated with
cross-sectional surveys. In particular, if they are carried out carefully, they have
38
Country
US
US
UK
US
UK
UK
Australia
UK
UK
Study/year
Lincoln
1974 [9]
Lutsky 1975
[10]
Taylor 1976
[11]
Gross 1980
[12]
Cockcroft
1981 [13]
Davies 1981
[14]
Schumacher
1981 [15]
Slovak 1981
[16]
Beeson
1983 [17]
Pharma
Pharma
Research
Research,
pharma
Research
Research
Research,
pharma
Mixed
Research
Facility
M, R, Gp,
Rb
LA
M
LA
M, R, Gp,
Rb, S
M, R, Rb,
Gp
LA
M, R, Rb,
Gp, C,
D, H
M, R, Rb,
Gp, H
Species*
62 (83%)
146 (NA)
121
(82%)
585
(NA)
179
(61%)
399 (100%)
474 (NA)
1293
(NA)
238 (NA)
N (%
response)
NA
NA
3 years
NA
NA
NA
NA
NA
NA
Average
duration of
exposure
24%
30%
32%
20%
27%
15%
23%
15%
11%
Any
5%
10%
4%
3%
12%
8%
9%
10%
5%
Chest
21%
23%
24%
11%
25%
15%
17%
15%
9%
Eye/
nose
Prevalence of allergic
symptoms (%)
Table 2. Prevalence studies from cross-sectional surveys (English language publications).
5%?
NA
33%
NA
NA
NA
NA
NA
NA
Mouse
11%
NA
-
NA
NA
NA
NA
NA
NA
Rat
32%
(IgE)?
15%
(SPT)
-
NA
16%
(SPT)
NA
NA
NA
10%
(SPT)
Any/other
Prevalence of sensitisation:
SPT or IgE (%)
Epidemiology of laboratory animal allergy
39
40
US
Israel
UK
UK
UK
Japan
UK
Bland 1986
[19]
Lutsky 1986
[20]
Platts-Mills
1987 [21]
Venables
1988 [22]
Venables
1988 [23]
Aoyama
1992 [24]
Cullinan
1994 [8]
Australia
Sweden
Agrup 1986
[18]
Bryant 1995
[25]
Country
Study/year
Table 2 (continued)
Research
Research
Research,
breeding
Mixed
Pharma
Research
Research
Research
Research
Facility
LA
R
R, M, Gp,
Rb, H, C,
D, P, Mn
R, M, Rb,
Gp
R, M, Rb,
Gp
R
R, M, Rb,
Gp
R, Rb,
Gp, C
M, R, Rb,
Gp, H, C
Species*
130 (NA)
323 (88%)
5641 (64%)
296 (NA)
138 (87%)
213 (NA)
90 (NA)
549 (93%)
101 (100%)
N (%
response)
NA
21 months
NA
8 years
9 years
NA
9 years
NA
NA
Average
duration of
exposure
56%
31%
23%
47%
44%
17%
7%
24%
30%
Any
22%
10%
6%
13%
11%
10%
4%
NA
20%
Chest
NA
22%
18%
NA
37%
7%
7%
NA
10%
Eye/
nose
Prevalence of allergic
symptoms (%)
NA
-
NA
NA
NA
-
NA
NA
18%?
Mouse
NA
10%
(SPT)
NA
NA
NA
12%
(SPT)
NA
NA
18%
Rat
NA
-
NA
17%
(SPT)
26%
-
NA
NA
any:19%
(SPT+IgE):
Rb: 11%,
Gp: 26%,
C: 31%
Any/other
Prevalence of sensitisation:
SPT or IgE (%)
Hayley L. Jeal, Meinir G. Jones and Paul Cullinan
Netherlands
Netherlands
Sweden
Netherlands
UK
France
Finland
UK
Poland
New
Zealand
Hollander
1996 [26]
Hollander
1997 [27]
Heederik
1999 [28]
Heederik
1999 [28]
Heederik
1999 [28]
LieutierColas 2002
[29]
Ruoppi
2004 [30]
Jeal 2006
[31]
Krakowiak
2007 [32]
Hewitt 2008
[33]
Research
Vets
Research
Research
Research
Research,
pharma
Research,
pharma,
training
Research,
training
Research,
pharma
Research,
pharma,
Research,
pharma,
LA
R, M, H,
Rb, Gp
R
R, M
R
R
R
R
R
M
R
50 (NA)
200 (NA)
689 (96%)
156 (61%)
113 (100%)
357 (88%)
219 (77%)
74 (82%)
398 (77%)
377 (77%)
458 (77%)
11 years
NA
8 years
6 years
NA
<4 years
<4years
<4 years
NA
10years
11years
22%
NA
22%
47%
39%
-
-
-
20%
10%
19%
4%
10%
NA
26%
4%
9 (3%)
5%
3%
NA
3%
6%
18%
14%
NA
42%
34%
10%
15%
12%
NA
9%
17%
4%
16%
(SPT)
-
NA
-
-
-
-
-
10%
(SPT)
-
2%
17%
(SPT)
11%
NA
12%
4%
8%
5%
17%
(SPT)
-
18%
(SPT)
Gp: 2%
H: 6%,
Gp: 13%,
Rb: 5%
-
NA
-
-
-
-
-
-
-
* M, mouse; R, rat; Rb, rabbit; Gp, guinea pig; H, hamster; D, dog; C, cat; S, sheep; Mn, monkey; LA, laboratory animals unspecified; SPT, skin prick
test.
NA, not available.
Netherlands
Hollander
1996 [26]
Epidemiology of laboratory animal allergy
41
Hayley L. Jeal, Meinir G. Jones and Paul Cullinan
the ability to examine the determinants of employees’ movements within or out
of a workforce. Furthermore (see below), they allow the measurement of relevant
workplace exposures, a particular advantage in an immunological disease such as
laboratory animal allergy where it is probably the case that very early exposures
determine the risk of sensitisation.
However, cohort studies are far more difficult to conduct well, and tend to be far
more expensive, than cross-sectional surveys. Probably for these reasons they have
been far fewer in number. Occasionally (e.g. [35, 36]) cohort studies are embedded
within routine surveillance schemes, potentially a far more efficient approach – and
certainly one that is underused.
Eleven published cohort studies are summarised in Table 3 with estimates of
disease and sensitisation incidence rates where these are available. As with the crosssectional surveys described earlier, the response rates for several are low – a serious
problem with any cohort design.
Some studies have been of very short duration and probably have produced
underestimates of true incidence rates. A further important limitation of many
studies is that they incorporate participants with previous occupational exposure
to laboratory animals. This effectively negates much if not all of the advantage of a
longitudinal approach over the cross-sectional survey. Some [35, 43] have restricted
analyses to, or included analysis of, newly exposed employees and so gained valuable insights. In a longitudinal study of pharmacological research employees in the
United States for example [35], the estimated incidence rate of laboratory animal
allergy was about 2.3 per 100 person years. In an analysis confined to employees
without prior exposure to laboratory animals, however, the estimated incidence rate
was about twice as high, suggesting an important degree of ‘selection out’ in that
workforce.
A note of further caution in relation to estimated incidence rates for laboratory
animal allergy in warranted. The immunological nature of this short-latency condition is reflected in a high incidence of disease shortly after first exposure – and probably a diminishing risk thereafter, under conditions of continuing similar exposure.
If this is true then rates derived across a longitudinal survey may hide differential
annual rates; few, if any, studies have been large enough to examine this in any
detail.
Surveillance schemes
Alternative methods of measuring the frequency of laboratory animal allergy depend
on routine surveillance statistics. Several countries – notably Finland, the UK and
France but also South Africa and parts of Spain, Canada and Australia – have established surveillance schemes for occupational asthma. Each measures disease that is
newly recognised and reported by specialised physicians, usually in occupational
42
US
US
UK
Kruize 1997 [41]
Fisher 1998 [42]
Cullinan 1999
[43]
US
Elliot 2005 [35]
Pharma
Research
Training
Research
Pharma
Pharma
Training
Training
Research
Pharma
Pharma
Facility
LA
M, R, Rb, Gp,
M, R, Rb
R
LA
LA
M, R, Rb, H,
Ho, P, Ch
LA
LA
R, M, Gp, Rb
M, R, Rb, Gp
Species*
495 (82%)
105 (NA)
387 (93%)
373 (89%)
342 (80%)
159 (NA)
99 (44%)
38 (100%)
29 (55%)
169 (70%)
383 (NA)
148 (100%)
n (% of
eligible
population)
12 years
2 years
44 months
7 years
b 5 years
10 years
18 months
7 months
2 years
Variable
1 year
Duration of
follow–up
2.3
6
–
–
0–10
1.9
6
0
6.5
12–37
15
Any
NA
–
2.7
3.5
NA
0.8
2
0
NA
NA
2
Chest
3
NA
9.6
–
7.3
NA
1.4
5
0
NA
NA
NA
Eye/
nose
1.32
NA
NA
4.1
NA
NA
5
NA
NA
NA
NA
Estimated
incidence of
sensitisation (SPT
or IgE) per 100
person years
* M, mouse; R, rat; Rb, rabbit; Gp, guinea pig; H, hamster; D, dog; C, cat; S, sheep; Ho, horse; P, pig; Ch, chicken; LA, laboratory animals
unspecified; SPT, skin prick test.
NA, not available.
Netherlands
De Meer 2003
[46]
Rodier 2003 [45]
Canada
Sweden
Renstrom 1995
[40]
Gautrin 2001 [44]
US
US
Kibby 1989 [38]
UK
Botham 1987
[36]
Das 1992 [39]
UK
Country
Davies 1983 [37]
Study/year
Estimated incidence of
allergic symptoms per 100
person years
Table 3. Estimated incidence rates of laboratory animal allergy from longitudinal studies.
Epidemiology of laboratory animal allergy
43
Hayley L. Jeal, Meinir G. Jones and Paul Cullinan
or respiratory medical practice; in some instances the schemes are closely linked to
compensation claims. They are of course entirely dependent on the presentation of
disease by an employee and its recognition and reporting by an appropriate specialist. Surveillance in this manner certainly leads to an underestimate of the true
incidence of occupational asthma; in the case of laboratory animal allergy this is
enhanced by the omission of cases without overt asthma.
Some surveillance schemes can be linked to national workforce denominators to
estimate occupation-specific incidence rates (Tab. 4). Such denominators are rarely,
if ever, specific to laboratory animal workers. Hence the rates from which they are
derived are a further underestimate of the true job-specific incidence. In the UK,
for example, the annual incidence rate of occupational asthma among ‘laboratory
assistants and technicians’ was estimated to be 0.24/1000, based on a workforce
of 127 478. A subsequent exercise to establish a more specific estimate of the size
of the laboratory animal-exposed workforce produced a figure of between 12 000
and 17 300 employees working with small mammals. From these were derived new
estimates of annual disease incidence of 1.26/1000 and 2.54/1000 for occupational
asthma and occupational rhinitis, respectively [47].
Analysis of reports from surveillance schemes in different countries also affords
the possibility of international comparisons (Tab. 4). Where they are available (but
see above), estimated annual incidence rates vary between 17 and 79 cases per
Table 4. Numbers of total cases of occupational asthma and laboratory animal asthma with
estimated annual incidence rates per million workers from surveillance schemes in seven
different countries.
All occupational asthma
Scheme
No. of
cases
Laboratory animal
asthma
Annual
incidence
No. of
cases
Annual
incidence
Laboratory
animal
asthma as a
proportion of
all cases
UK (1989–1990) [48]
1985
20
50
188
2.5%
France (1996–1999) [49]
2178
24
27
NA
1.2%
Finland (1989–1995) [50]
2602
17
52
116
2.0%
South Africa (1997–1999)
[51]
324
18
3
NA
0.9%
Quebec (1992–1993) [52]
287
42–79
19*
329**
7%
Catalonia, Spain (2002) [53]
174
NA
7
NA
4%
Australia† (1997–2001) [54]
170
NA
4
NA
2.4%
*Occupational asthma to ‘laboratory and farm animals’ in **’agricultural and related service industries’
†
Victoria and Tasmania
NA = not available
44
Epidemiology of laboratory animal allergy
million workers; the last (highest) figure, however, also includes agricultural workers. The proportions of all registered cases of occupational asthma that are attributed to laboratory animal exposures are remarkably consistent between approximately 1% and 7%, the lowest figure being for three provinces in South Africa.
Aside from the professional surveillance schemes above, estimates of the incidence of laboratory animal allergy may be made from counts of claims for statutory
compensation or, through the courts, for personal injury. The obvious weaknesses in
each of these is likely to compound the problems of under-ascertainment described
above.
Risk factors
The imperative to reduce the incidence of laboratory animal allergy has produced a
focus on the study of modifiable risk factors. The most important of these is believed
to be allergen exposure within the workplace. Most allergen exposure-response
studies have, like those of disease frequency, been carried out in cross-sectional
occupational populations. A summary of these (n = 18) together with the findings of
five cohort studies is displayed in Table 5. In addition, where it is available, information on disease latency is provided. The evidence that laboratory animal allergy is
usually a condition of short latency is both consistent and strong.
Allergen exposure
‘Exposure’ has, in most cases, been assessed by job title and only occasionally by
direct measurement of airborne allergen. The use of ‘zoning’ techniques whereby
employees in different jobs are grouped by their likely exposures (e.g. into ‘scientist’,
‘animal technician’ and ‘other’) allows job title to be a good, albeit broad, proxy of
direct measurement [55]. Where proxies are used as the main indicator of exposure,
it is helpful if they are supplemented by quantitative exposure information. Neither
approach, however, has proved to be a good indicator of the variability in exposure
‘quality’; the exposure of animal technicians, for example, who carry out the dayto-day care of animals, is likely to be more consistent than that of scientists whose
experimental protocols generally cause a far more variable exposure pattern.
In general it has been more difficult in cross-sectional surveys to demonstrate any
relationship between allergen exposure – however defined – and disease risk. The
reasons for this have been discussed above and probably relate primarily to survival
processes including those that determine survival within a particular job within a
workplace. In a survey of UK research workers [8], no relationship between disease
prevalence and current exposure was observed; however, such was evident when
exposure at the time of onset of disease was examined, suggesting that employees
45
46
Species*
Mixed
Mixed
Mixed
R
Mixed
Mixed
Slovak 1981 [16]
Beeson 1983 [17]
Bland 1986 [19]
Platts-Mills 1987
[21]
Venables 1988a
[22]
Aoyama 1992
[24]
Mixed
Cockcroft 1981
[13]
M
Mixed
Gross 1980 [12]
Schumacher 1981
[15]
Mixed
Taylor 1976 [11]
Cross-sectional surveys
Study/year
5641
138
213
549
62
146
121
179
399
474
n
Job category,
frequency,
# species
Job category,
duration of
exposure
Job categories
Job category,
frequency
Duration of
exposure
Job category
Frequency/
duration of
exposure
Job category
Frequency
of entry into
animal house
ND
Exposure
measurement
33% b 1 year,
70% b 3 years
ND
Mean 2.5 years
ND
ND
Asthma: 66% b 3 years
usually <1 year
High exposed groups <
medium exposed
Average 11 months. “LAA
most likely to occur within 6
m and rarely > 2–3 years”
“No increase in incidence of
LAA after 2 years”
Latency
Prevalence of LAA increased with higher frequency of
exposure and with increasing # species handled.
No significant association with job categories
Non-significant inverse trend by duration of exposure for
prevalence of LAA
Sensitisation: 0% (low exposure), 6% (medium), 20%
(high).
Duration is less important than exposure
Dose effect for frequency in low/moderate but not in
high exposure group.
No. of species handled is a risk factor for LAA
No significant difference in duration of exposure
between LAA and non-LAA cases
Asthma cases confined to high exposure group
Neither frequency nor duration of exposure significantly
related to sensitisation or symptoms.
ND
ND
ND
Exposure-response
Table 5. Cross-sectional and cohort studies of the relationship between exposure and the risk of laboratory animal allergy.
Hayley L. Jeal, Meinir G. Jones and Paul Cullinan
Mixed
R
R
Fisher 1998 [42]
Heederik 1999
[28]
Lieutier-Colas
2002 [29]
Mixed
Krakowiak 2007
[32]
R
Mixed
Davies 1983 [37]
Kibby 1989 [38]
Cohort studies
R
Jeal 2006 [31]
R, m
R
Hollander 1997
[27]
Ruoppi 2004 [30]
R
Cullinan 1994 [8]
450
142
200
689
156
113
650
159
398
323
Aeroallergen
measurement
ND
Frequency
Job category,
# rats handled
Frequency of
handling
Aeroallergen
measurement
Aeroallergen
measurement
Intensity of
exposure
Aeroallergen
measurement
Aeroallergen
measurement
ND
Symptoms within 0.5–12
years – rhinitis preceded
asthma
ND
ND
ND
ND
ND
ND
ND
ND
Duration unrelated to LAA
Positive association between LAA and intensity of
exposure (PR = 1.75; 95% CI, 1.06–2.39; p = 0.03)
Positive association between LAA and weighted job
exposure (PR = 1.58; 95% CI 1.00–2.50)
ND
Exposure-response relationship for symptoms (OR 50.2;
95% CI, 2.84; 884.99)
High-exposure attenuation of exposure–response
relationship for sensitisation and symptoms
Exposure-response relationship between intensity of
exposure and development of respiratory disease.
No relationship between rat exposure and development
of sensitisation or symptoms
Risk of sensitisation increased with exposure intensity.
Atopics had elevated risk of sensitisation at low allergen
exposures.
High exposure not a significant predictor of LAA
In those exposed <4 years – prevalence of sensitisation
in low, medium and high exposure groups were 4.1,
5.0 and 7.2 times higher than control group. Exposure
–response relationship steeper in atopics
Prevalence of LAA symptoms related to intensity of
exposure. Stronger in atopic subjects
Epidemiology of laboratory animal allergy
47
48
LAA, laboratory animal allergy
Frequency of
handling
Mixed
Eliott 2005 [35]
495
Time in contact
417
Mixed
Exposure
measurement
Rodier 2003 [45]
n
Aeroallergen
measurement
Species*
Cullinan 1999
[43]
Study/year
Table 5 (continued)
ND
ND
Median: skin, eye/nose
12 months, chest 18 months
Latency
Risk of LAA increased with duration of exposure to
animals and work in animal-related tasks
Contact time associated with the incidence of
rhinoconjuctivitis in dose-dependent manner
In those exposed < 2 years, exposure related to
development of symptoms – but attenuated at highest
exposure. Relationship stronger in atopics.
Exposure-response
Hayley L. Jeal, Meinir G. Jones and Paul Cullinan
Epidemiology of laboratory animal allergy
with symptoms had moved away from jobs of higher exposure. Similar factors
presumably explain why duration of exposure appears irrelevant [38] – or even
inversely related to risk [22].
Many cohort studies of laboratory animal employees have been set up to examine exposure-response relationships and thus have done so with greater attention to
detail. Some [43] have had this aim as primary, others [36, 42] in order to examine
changes in disease incidence in relation to primary preventive programmes. Broadly,
their findings suggest that higher allergen exposure intensities are related to the
risk of laboratory animal allergy – with some important modifying influences (see
below). What is far less clear is the detail of such a relationship and in particular the
existence – and level – of any threshold of exposure below which there is no measurable risk. This is a problem common to any immunological outcome, reflecting
in part the wide range of individual susceptibility. Arguably this is an issue that will
not be amenable to further epidemiological study.
A recent and interesting observation is that the relationship between exposure
intensity and risk, which is almost certainly non-linear, may also not be monotonic.
Thus, there is some evidence [31, 43] that at highest exposures there is a degree
of attenuation in risk; this may reflect qualitative differences in exposure (e.g.
‘constant’ vs ‘intermittent’), differences in exposure route or even a phenomenon
of high-dose ‘immunotolerance’. The last of course – if established with certainty –
would have interesting implications for occupational health practice.
Atopy
Atopy, the tendency to develop immediate-type immune responses to environmental
aeroallergens, is a well-documented risk factor for the development of laboratory
animal allergy [8, 13, 19, 27], its relative risk being of the order of 3.0–4.0 [8, 13,
19, 27, 41]. Cross-sectional studies generally report higher risk estimates than do
those of longitudinal design, perhaps a reflection of co-sensitisation. In addition,
atopic employees are more likely to develop occupational asthma as a result of
exposure [13, 41], and are more likely to be absent from work or transferred to
another job because of symptoms of laboratory animal allergy [41]. Indeed, the latter observation suggests that survival is further influenced by atopic status, in which
case its true relative risk may be higher than is commonly measured. The onset of
symptoms from laboratory animals following first exposure is probably shorter in
atopic employees than it is in those who are not atopic [36, 41]. For example, Kruize
et al. [41] reported that the mean latency for laboratory animal allergy was significantly shorter in atopics (45 months) than in non-atopics (109 months).
Furthermore, atopy may confer quantitative differences in the response to allergen exposure in the laboratory. Several studies suggest a stronger exposure response
for the development of laboratory animal allergy in atopic than non-atopic workers
49
Hayley L. Jeal, Meinir G. Jones and Paul Cullinan
[8, 27, 28, 41, 43], although this is not an entirely consistent observation and probably dependent on both exposure levels and any definition of atopy. Differences may
also reflect lower outcome rates – and thus less statistical power in non-atopic subgroups. Kruize et al. [41] reported similar exposure-response patterns in atopic and
non-atopic groups, but a stronger relationship in those who were atopic. Similarly,
other studies suggest interactions between allergen exposure and atopy whereby,
in general, exposure-response relationships are steeper for workers with atopyassociated risk factors [8, 27]. Heederik et al. [28], on the other hand, reported a
flatter association in atopic workers; this finding probably reflects exposures above
an important threshold for atopic workers who, at the lowest level of exposure, had
a more than threefold increase in risk of allergy.
Clearly atopy is a strong risk factor in the development of laboratory animal
allergy and the question arises as to whether it could be used as a predictive tool.
In their longitudinal study of pharmaceutical research workers, Botham et al. [36]
observed that laboratory animal workers who developed symptoms during their
first year of exposure were mainly atopic, but that the majority of atopic subjects
remained non-symptomatic during the first year of exposure. The number of atopics
becoming symptomatic in the second and third year of exposure was small with an
increasing proportion of non-atopics developing laboratory animal allergy. Similarly, Slovak and Hill [56] in an examination of several different methods of defining
‘atopy’ concluded that none had sufficiently high predictive sensitivity or specificity.
A more recent study has essentially confirmed these findings [57]; although atopy is
strongly associated with the development of laboratory animal allergy, its predictive
value is low and most employees with atopy – currently a high proportion of laboratory animal workers – will not develop a specific sensitisation. Thus, the exclusion
of atopic people from working with laboratory animals seems to be insufficiently
discriminatory as a factor to be considered as a means of screening for susceptible
individuals.
Human leucocyte antigen
There have been few studies investigating the association of HLA genes and laboratory animal allergy. The first of two relatively small studies found statistically significant associations with HLA-B15, -DR4 and (inversely) -B16 and sensitisation to
rat urine [58]. The second reported an excess of HLA-DR4, -DR11 and -DRw17 in
human T lymphocyte responses to the major mouse allergen, Mus m 1 [59].
In a relatively large case (n = 109) referent (n = 397) analysis of a cross-sectional
survey of pharmaceutical researchers, HLA-DR7 was associated with sensitisation,
respiratory symptoms at work and most strongly with the combination of sensitisation and symptoms [60]. HLA-DR3 was found to be protective against sensitisation.
Furthermore, amino acid analyses of HLA-DR7 and -DR3 indicated a biologically
50
Epidemiology of laboratory animal allergy
plausible explanation for the associations found. There was no evidence of any
modification by exposure of the association between HLA-DR7 and sensitisation to
rat urinary protein, or respiratory symptoms at work.
In the same study, the risk estimate of being sensitised to rat urinary protein was
almost doubled in the presence of HLA-DR7; this risk was lower than those associated with atopy (fivefold) or a crude estimate of exposure (fourfold). These figures
suggested that approximately 40% of occupational asthma in that population study
could be attributed to HLA-DR7; in comparison, attributable proportions for atopy
and daily work in animal house were 58% and 74%, respectively.
Conclusion
Laboratory animal allergy is common and an important occupational health issue
for the research, pharmaceutical and toxicological sectors. In most settings where
there is regular contact with laboratory animals – chiefly small mammals – the prevalence of specific sensitisation is around 15% and the prevalence of clinical allergy
around 10%. These figures probably underestimate the true risk of disease since
epidemiological studies of the disease have been beset by response and survivor
biases. Allergen exposure appears to be the most important modifiable risk factor;
however, the effects of such exposure seem to be modified importantly by individual
susceptibility. Laboratory animal research shows no signs of becoming less common
and an increasingly susceptible (atopic) population is likely to be recruited into such
work. Future studies should be designed to take into account the inherent biases of
occupational epidemiology, to study in detail the immunological mechanisms that
underlie sensitisation and tolerance, and to identify early biomarkers of each.
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55
Population-attributable fraction for occupation and asthma
Kjell Torén1 and Paul D. Blanc2
1
Department of Occupational and Environmental Medicine, Sahlgrenska University Hospital,
Göteborg, Sweden
2
Division of Occupational and Environmental Medicine, University of California San
Francisco, San Francisco, California, USA
Abstract
Here we review the use of the concept of population-attributable risk (PAR) of asthma associated
with occupation and give the context for its interpretation. For asthma there is major interest in
delineating the “burden of disease”, because such assessments can inform health care priorities,
intervention policies, and assessment of impact once such steps are implemented. For asthma,
the burden of disease from occupational factors is of particular relevance because asthma is a
common disease that affects persons of working age and because asthma can be associated with
major morbidity and economic cost. In 1999, we carried out a systematic review of the published
literature relevant to the occupational PAR in asthma. Of 23 published PAR estimates identified,
the median value was 9%, but among those, the 10 estimates based on population-based studies
yielded a median PAR estimate of 15%. A few years later a task force of the American Thoracic
Society (ATS) summarized the general population-based studies in this field, ending up with a
median value of 15%. We have summarized data from publications that have appeared since 2000
and the median value from these publications is 14.4% (range 6–31%).
We show in this analysis that 3 in 20 cases of asthma among adults are likely to be linked to
occupational factors. Longitudinal incidence-based estimates, which should be the most reliable,
suggest that, if anything, the actual PAR may even be higher. Other measures such as impaired
quality of life and economic disadvantage are also important, but are not addressed in this review
as there is lack of studies. This points to future research needs to address this knowledge gap in the
field of work-related asthma. In the meantime, the consistency of the PAR data that we do have
certainly underscores the importance of workplace factors in the overall burden of asthma.
Introduction
The aim of this chapter on the population-attributable risk (PAR) of asthma associated with occupation is to provide both the data germane to this topic and a context
for its interpretation. For chronic conditions generally, there is major interest in
delineating the “burden of disease”, because such assessments can inform health
care priorities, intervention policies, and assessment of impact once such steps
are implemented. For asthma, estimating the burden of disease from occupational
Occupational Asthma, edited by Torben Sigsgaard and Dick Heederik
© 2010 Birkhäuser / Springer Basel
57
Kjell Torén and Paul D. Blanc
factors is of particular relevance because asthma is a common disease that affects
persons of working age and because asthma can be associated with major morbidity and economic cost. Moreover, certain agents have long been recognized to cause
new-onset asthma among persons exposed at work, making occupational asthma
a widely recognized medical entity. Because of these factors, there is considerable
accumulated evidence pertinent to the population burden of asthma attributable
to occupation. In this chapter, we first address general epidemiological aspects of
attributable risk estimation. We then review the body of evidence that yields such
attributable risk estimates, summarizing previous systematic reviews of the literature and presenting data from key analyses that have appeared in the last 10 years.
Finally, we place these data in their public health context.
Estimating PAR
The relative risk (RR) and the odds ratio (OR), the two risk measures most widely
familiar to non-epidemiologists, compare the likelihoods of disease among exposed
as opposed to non-exposed groups. The measure “population-attributable risk”,
PAR, is a less familiar construct and, to a certain extent, a less intuitive one. The
PAR takes into account both comparative risk (RR or OR) and the frequency of
exposure in the population studied. Based on these two components, or risk and
exposure, the PAR estimates the proportion of the disease burden among exposed
people that is likely to have been caused by the exposure of interest. The PAR
is commonly interpreted as the amount of disease that would be prevented (the
reduced burden) were the risk factor in question to be removed altogether.
A synonymous term, “population-attributable fraction” (PAF) is preferred by
some authors; the expanded term PAR percent also is frequently used. In addition
to a lack of familiarity with the construct and inconsistencies in terminology (PAR,
PAR%, PAF) that can lead to unnecessary confusion, PAR estimates have other
attributes that further complicate their interpretation. As noted above, the PAR
estimation can utilize either an RR or OR value in its calculation, but the exposure
prevalence (which is a major driver in the ultimate value derived) also has two variants: either the proportion of cases exposed or the overall population exposure rate.
Provided that either the RR or OR and that either the case exposure rate or overall
exposure proportion has been provided, then the PAR can be estimated post hoc
from a published study, even if it failed to include an explicit PAR calculation. If
the RR or OR used is derived from a multivariate predictive model, then the point
estimate of the PAR does reflect the role of any confounding variables included in
the model. Post hoc calculations without access to the original data set, however,
cannot take into account the variance of such covariates, and thus cannot estimate
confidence intervals (CI) around PAR estimates derived from published risk and
exposure values.
58
Population-attributable fraction for occupation and asthma
A key attribute of the PAR metric is that, for any given outcome with multiple
risk factors, the sum of the estimated risk factors derived form a multivariate model
can add up to more the 100% of the risk [1]. This phenomenon is consistent with
the effects of risk factors that are inter-related in a more than additive fashion.
Although there are no established examples of this in the case of occupational
asthma, such a relationship could be possible in the example of estimates for the
PAR for chronic obstructive pulmonary disease (COPD) associated with occupation
and smoking [2]. There are also other conceptual as well as computational nuances
to the estimation and interpretation of attributable risk that are beyond the scope of
this chapter; these issues are addressed in a seminal paper by Greenland and Robbins, as well as in a recent review by Benichou [3, 4].
It should also be kept in view that estimates of proportional attribution can be
arrived at by other means, although the limitations of such approaches have to be
taken into consideration. This is particularly relevant to the occupational asthma
literature where incident occupational asthma may be estimated based on a clinically cased attribution, and the “numerator” so generated is divided by the general
incidence of asthma from all causes. This proportion can be approached as one form
of attributable risk estimate, bearing in mind the limitations of under-diagnosis or
over-attribution. Using occupational asthma surveillance data for the numerator in
such an exercise (taking the denominator from age-equivalent population incidence)
is especially fraught with limitations of under-diagnosis (under-reporting).
Previous systematic reviews of occupationally associated PAR for asthma
In 1999, we carried out a systematic review of the published biomedical literature
dating back to 1966 relevant to the occupational PAR in asthma [5]. This review
applied very generous inclusion criteria that captured full publications including
PAR estimates and those that only provide data that allowed post hoc calculation,
as well as published letters and abstracts and even consensus-based estimates in
reviews. Of 23 published PAR estimates identified the median values was 9%, but
among those, the 10 estimates based on population-based studies yielded a median
PAR estimate of 15%. A series of estimates derived post hoc from 8 other population-based studies yielded a somewhat higher median PAR value of 20%. Because
of the heterogeneity of the data set, we also applied a quality rating schema to the
publications. This yield a weighted mean PAR of 15% (n = 28 values, excluding 3
non-data-based estimates); the median PAR value among the 12 studies that scored
highest in quality was also 15%. Finally, we also extrapolated PAR estimates based
on surveillance data for occupational data from 12 systems and presuming an adult
general incidence of 1 per 1000 per year. The median PAR extrapolation using that
approach was 5%. Of note, in that subset, Finish surveillance-based data yield an
extrapolation close to overall central tendency of the data, in the 14–17% range.
59
Kjell Torén and Paul D. Blanc
Shortly after that systematic review appeared, a task force of the ATS embarked
on a similar data synthesis intended to summarize the general population-based
studies in this field. This eventually led to the formal adoption (2002) of a statement, Occupational Contribution to the Burden of Airway Disease [6]. The ATS
systematic review used stricter selection criteria, excluding consensus estimates,
letters, and abstracts. Many, but not all of the publications in the ATS review also
had been included in the previous review. Even with this different approach, however, the PAR estimates for asthma summarized in the ATS statement also yielded a
median value of 15%.
The ATS estimate of 15% was based on 21 different publications. Of these, 7
were asthma cohorts or case series in which the estimated occupational contribution
was not based on an epidemiological estimate, but rather the proportion of occupationally attributed cases to all asthma cases. The remaining 14 studies were all
population-based and either reported a PAR estimate or provided data from which
a PAR estimate could be calculated for the purposes of the ATS review. Table 1 lists
the findings from those 14 studies, many of which were quite large in size [7–20].
One study was based on an analyses of the European Community Respiratory
Health Survey (ECRHS I), including 22 countries from three continents [7]. The
range of the PAR was wide from 5% to 51%, with a mean value of 19.5%.
Table 1. The occupational contribution to the burden of asthma. General population studies
reviewed in the ATS document
Endpoints
Bronchial hyperreactivity and
symptoms
Number of
studies
PAR median
PAR range
Reference
1
10%
NA
[7]
Clinical diagnosis
6
34.5%
5–51%
[8–13]
Self-reported asthma, including
physician-diagnosed
7
19%
15–29%
[14–20]
Total
14
19.5%
5–51%
[7–20]
Recent longitudinal studies of PAR
The variability in previous PAR estimates, even with a central tendency in the
15–20% range (depending on the study range included) underscores the value in
evaluating additional relevant studies that have appeared in the interim. Because we
have the benefit of such a rich data set of previously analyzed material, the field has
sufficiently evolved so that more restricted analysis is appropriate. To that end, we
60
Population-attributable fraction for occupation and asthma
emphasize here estimates derived from general population sampling. Moreover, we
highlight in particular data obtained through longitudinal follow-up, as opposed to
cross-sectional analyses.
Table 2 summarizes the data from 12 publications relevant to occupational risk
for asthma based on general population studies or other systematic recruitment
that have appeared since 2000 [21–32]. Overall, the studies summarized in Table 2
support and amplify the findings of the earlier ATS statement. In total, these studies represent 51 294 subjects, excluding the large longitudinal cohort study from
Finland, which included 829 351 additional subjects [25]. For the data shown in
Table 2, we derived all of the PAR estimates, based either on the published PAR
value or by calculating the PAR using the published risk estimates and exposure
proportions according to the same methods that were also used in the ATS statement [6].
Three of the studies (Tab. 2) are prospective longitudinal investigations, based
on follow-up of previous general population samples [21, 24, 25]. The Norwegian
study represents a follow-up of a general population sample of 3886 subjects investigated in 1985 [21]. The age at study baseline in 1985 ranged from 15 to 70 years.
The study participants were investigated 10 years later, 1996, with a new questionnaire that was completed by 2819 subjects (89% of the baseline group). Asthma
at follow-up was defined as an affirmative answer to “having been hospitalized
or treated by a physician for asthma”. The occupational exposure was defined
by the self-report questionnaire item “Have you ever had a workplace with much
dust or fumes in the air?” The exposure prevalence was 28%, with a considerable
difference between males (44%) and females (13%). The risk for incident asthma
during follow-up in relation to ever exposed to dust or fumes was analyzed using
logistic regression models, yielding a 60% increased odds of disease associated with
exposure (OR 1.6, 95% CI 1.01–2.5). The PAR associated with dust or fumes and
incident asthma, presented in the published paper, was 14.4% (95% CI 1.2–27.6).
Risk estimates stratified by sex were not included. Strengths of this study, over
and above its relatively large, population-based cohort, include the longitudinal
design, thus assessing incident asthma, the high subject retention rate, mitigating
selection effects, and the provision of a PAR estimates that includes 95% CI values. Because the exposure and incident asthma occurred over the follow-up period
is not analyzed in terms of specific time points, a potential study weakness lies in
lack of a temporal anchor (i.e., in some cases exposure might have followed disease
onset). Because of job stability and the low likelihood that persons with asthma will
migrate from low exposure to high exposure jobs this concern is more theoretical
than practical. In addition, risk estimates stratified by sex were not provided. Other
weaknesses include the lack of sex-stratified risk estimates and the reliance on a
single exposure metric.
The second study with high quality is the follow-up analysis of the European
Respiratory Health Survey (ECRHS II) [24]. The ECRHS is an international cross-
61
Kjell Torén and Paul D. Blanc
Table 2. The occupational contribution to the burden of asthma: Population-based studies
published since 2000
Ref. N
Design
Country
Asthma definition
Occupational exposure
21
2819
Longitudinal
cohort
Norway
Self report
of physiciandiagnosed asthma
Self-reported exposure to 14.4%
much dust or fumes
22
13 826
Crosssectional
cohort
South
Africa
Self report of
physician or nurse
diagnosed asthma
Ever regularly exposed
to smoke, dust, fumes or
strong smells or worked
underground in a mine
13.6%
23
1922
Crosssectional
cohort
Brazil
BHR and workrelated asthma
symptoms
Self-reported exposure
to vapor, gas, fumes,
chemical products, paints
and humidity
22.9%
24
6837
(3994,
BHR
tested
subset)
Longitudinal
cohort
International
Asthma symptoms
or asthma
medication;
above definition
+ BHR
Job Exposure Matrix
defined occupational risk
11%
23%
Med = 17%
25
89 2351
LongiFinland
tudinal
cohort of all
employed
Finns
Physician diagnosis Occupations a priori
based on asthma
classified as exposed
symptoms and at
least one criteria of
airway reversibility
29%
(Males)
17%
(Females)
Weighted =
22%
26
5331
Crosssectional
cohort
New
Zealand
Self-report
of physiciandiagnosed, adultonset asthma
Occupations a priori
classified as exposed
9.5%
27
14 151
Crosssectional
cohort
France
Dyspnea with
wheezing or
asthma attacks;
asthma onset after
start of current
job
Self reported exposure;
occupations a priori
classified as exposed
using a JEM
9%, 14%;
1%; 3%
Med = 6%
28
376
CrossFrance
sectional
case control
Specialist physician Occupations a priori
diagnosis
classified as exposed
using a JEM
10%
29,
30
6827
Crosssectional
cohort
Self-report
of physiciandiagnosed asthma
and work-related
symptoms
36.5%;
26%
Med =
31%
62
USA
Industries a priori
classified as exposed;
Occupations a priori
classified as exposed
PAR
Population-attributable fraction for occupation and asthma
Table 2 (continued)
Ref. N
Design
31
566
32
1482
Country
Asthma definition
Occupational exposure
PAR
CrossSweden
sectional
case control
General MD
diagnosis
Occupations a priori
classified as exposed
18%
Crosssectional
cohort
Self-report of MD
diagnosis
Self-report of exposure;
Occupations a priori
classified as exposed
using a JEM
17%; 5%
Med =
11%
USA
BHR, Bronchial hyperreactivity measured by methacholine challenge; JEM, job exposure matrix;
Med, midpoint or median value
sectional investigation drawing on data from 28 centers in 13 countries. At baseline
data collection (1990–1995), each center mailed a questionnaire to 3000 randomly
selected subjects aged 20–44 years of age. From the responders there was further
selection of a random smaller sample and a sample enriched with subjects with
asthma and asthma symptoms. At baseline, a cross-sectional analysis was performed
observing increased risks for asthma among farmers, painters and cleaners, and this
was included in the ATS review [6]. Ten years later, follow-up was performed in
which the participants completed extensive questionnaires including detailed occupational histories covering interval job duties and potential exposures. Subjects with
asthma, wheezing and dyspnea at baseline were excluded from the analysis in order
to study incident disease. Asthma during follow-up was defined in several ways,
but the most restrictive definition used reporting an asthma attack or having used
asthma medication in the 12 months preceding the follow-up interview, in combination with a positive methacholine-challenge test at the follow-up visit. Workrelated exposure was assessed by linking the occupations held during follow-up to
an asthma-specific job-exposure matrix (JEM) used in the previous cross-sectional
analyses. A second measure of risk was based on broadly classified “high-risk”
occupations. The reported PAR of the JEM-classified occupational exposure for
new-onset asthma was 23% (95% CI 1–40%). The broader occupational risk definition yielded a slightly higher PAR estimate of 26%. Using a less strict definition of
asthma that did not include methacholine responsiveness, the estimated PAR (JEMbased exposures) was 11% (95% CI 1–20%). This analysis allowed utilization of a
larger study number (6788 vs 3994). The strengths of this study, in addition to its
large, international scope and its longitudinal design, include the multiple measures
of exposure and the conservative (as well as more liberal) definitions of disease.
One limitation in the ECRHS is its low overall follow-up successful response rate
of 58%, and the further loss of subjects in the methacholine-based analyses. In
63
Kjell Torén and Paul D. Blanc
addition, CIs for the PAR estimates were not provided nor was PAR estimated for
sex-specific strata.
The Finnish study included in Table 2 was based on follow-up of three cohorts
of employed Finns aged 25–59 years at baseline [25]. The cohorts were defined
1985, 1990 and 1995 and followed for 5 years each. Hence, by design these cohorts
do not overlap in time. Onset of asthma during follow-up was obtained from a
National Register for Reimbursement, based on asthma medication cost coverage. To be qualified for reimbursement, a physician must certify a valid diagnosis
of asthma including objective documentation of variable airway obstruction or
hyperresponsiveness (reversible FEV1, serial peak flow measurements, or a positive
methacholine-challenge test) and the presence of symptoms consistent with disease.
Subjects with asthma at baseline were excluded from the analysis. Work-related
exposure was defined on the basis of certain occupations held at baseline and considered a priori to carry increased risk of causing asthma. Incidence rates of asthma
in each occupation were estimated, and incidence ratios using log-linear models
adjusting for age were calculated. The PAR for occupational exposure and newonset asthma, provided in the published study results, was 29% (95% CI 25–33%)
for men and 17% (95% CI 15–19%) for women. This study has high internal and
external validity, utilizing national registry data. One weakness is that the study is
biased towards more severe asthma, given that only cases reimbursed for medication are included. This is counter-balanced by a reduction in classification error
for disease in the direction of non-asthmatics being classified as ill. In addition, the
broad, occupation-based exposure is a fairly crude metric. Finally, although the
study provides sex-stratified PAR estimates with accompanying CIs, no calculation
of attributable risk is provided for males and females combined. A weighted PAR
value of 22% can be derived from the data.
Taking the three studies above as yielding the highest quality PAR estimates, the
summary values to be considered are: 14%, 11–23% (depending on the asthma
definition, the mid-point is 17%) and 22%.
Cross-sectional studies
All of the remaining nine studies whose results are summarized in Table 2 are
cross-sectional rather than longitudinal [22, 23, 26–31]. Some yielded multiple PAR
estimates using differing measures of exposure or asthma outcome or both, including two published analyses of the same national survey data, one based on industry
and one based on occupation [27, 29, 30, 32]. Where multiple PAR values were
presented, Table 2 also provides a mid-point (median) value. All but two studies
explicitly presented a PAR estimate; the values were calculated for these [23, 28].
The eight summary PAR values yielded by these nine cross-sectional studies
range from 6% to 31%, with a median of 12.4%. The heterogeneity in results is
64
Population-attributable fraction for occupation and asthma
not surprising. The definitions of asthma differed considerably. Of particular note,
the highest PAR estimate was derived from a study that defined asthma as both the
report of a physician’s diagnosis and self-report of work-related symptoms; this is
treated by the authors as a measure of “work-related asthma” [29, 30]. In general,
JEM-based PAR estimates were lower than those based on self-report: 1–3% compared to 9–14% in one study and 5% compared to 17% in another [27, 32].
One the studies shown did not provide risk and exposure data to yield a classic
PAR estimate, but rather attributable risk based on the number cases of adult onset
asthma with work-related symptoms asthma symptoms and onset of new asthma on
that job [23]. The 22.9% PAR in that series is the second highest estimate among the
cross-sectional studies. This study is special interest, however, because it represents
one of only two estimates from studies in developing economies, the other being a
PAR of 13.6% from South Africa [22].
Cross-sectional studies of asthma broadly defined to include onset at any age
may be at risk of under-estimating occupational risk. To the extent that persons with
life-long asthma either manifest no association with workplace factors or self-select
into lower exposure jobs, this will bias to the null or even a negative occupational
association. Even limited to adult-onset asthma, cross-sectional analyses ascertaining current occupations rather than the job held at the onset of disease run the risk
of survivor bias towards the null. Cross-sectional studies may also face reporting
biases if they depend on self-report of exposure, although this phenomenon may be
less important that sometimes presumed [33].
If all 11 summary PAR estimates from Table 2 are considered together, the
median value is 14.4% (range 6–31%). Once again, this wholly in line with previous ATS estimate.
Other data sources
There are also a few additional reports not included in Table 2 that, nonetheless,
should be mentioned. An analysis of the Singapore Chinese Health Study included
52 325 subjects [34]. Although this study does not provide PAR estimates, it does
include risk estimates for adult-onset asthma for three categories or workplace
exposures; dusts, smokes, and vapors. Although these three exposure categories
yield PAR estimates of 2.7,%,1.7% and 4.2%, respectively, it is not clear to what
extent the exposure categories overlap and only for vapors does the 95% CI for the
OR exclude 1.0.
There have also been two recent U.S. studies of asthma incidence in which an
attribution of work-relatedness was made. In one study of incident adult asthma in
a large health maintenance organization (HMO) data set (203 701 person years of
observation) concluded that 33% of incident asthma (which could include “recurrent” asthma previously in remission) was work-related [35]. Another large HMO
65
Kjell Torén and Paul D. Blanc
study (109 125 person years of observation) found that 24% of the cases had at
least moderate evidence of an occupational trigger [36]. These studies have limitations due to subject participation in the structured interviews forming the basis of
attribution, a selection effect that may in part account for the relatively high proportional attributions.
Finally, it should be noted that occupational disease registries continue to provide estimates of occupational asthma incidence, which can be used to extrapolate
an attributable fraction as a proportion of incidence among all persons of working
age. Our 1999 extrapolations used registry and other surveillance data from Canada
(British Columbia and Quebec), the U.S. (California and Michigan), the United
Kingdom (including Shield and Sword), Finland, Sweden, and Germany [5]. Since
that time, surveillance-based data (annual rates per 100 000 workers) have been
reported from Norway (10.1), France (2.4), Belgium (2.4), Italy (Piedmont region,
2.4), Spain (Catalonia, 7.7), Australia (3.1), New Zealand (3.1), and South Africa
(1.3 overall; 3.8 from the Western Cape) [37–44]. Even assuming a relatively low
general asthma incidence of 100 per 100 000 in adults of working age, these rates
would equate to an attributable proportion of only 1–10%. It is well recognized,
however, that such registry data fail to capture the majority of true cases. For
example, data from Finland indicate that, even after excluding officially recognized
occupational asthma cases, excess risk of disease was still evident on epidemiological grounds; the remaining risk was consistent with under-detection of one half to
two-thirds of cases proportionally, even for well-recognized risk groups such as
bakers, fur workers, and painters [45]. Consistent with this, survey data from three
U.S. states found that, although 5.8% to 6.1% of adults with asthma had been told
that by a physician that their condition was work related, the total increased to
7.4–9.7% if the respondents own assessment was included, an incremental increase
proportionally of up to two-thirds greater prevalence [46]. Thus, it should be presumed that any PAR value extrapolated from registry sources would be a woeful
underestimate.
Conclusion
Prior systematic reviews of the literature identified a wide range of estimates for
the PAR for occupational exposures in asthma, but with a central tendency close to
15% [5, 6]. As we have shown, emerging data continue to support the estimation
that 3 in 20 cases of asthma among adults are likely to be linked to occupational
factors. Moreover, longitudinal incidence-based estimates that should be the most
reliable suggest that, if anything, the actual PAR may even be higher.
Certain limitations of this analysis should also be borne in mind. First of all,
we have not addressed the burden of work-aggravated asthma, i.e., pre-existing
asthma made worse by work. Epidemiological analysis of this complex problem
66
Population-attributable fraction for occupation and asthma
is challenging and far beyond the scope of this review. It has been suggested that
PAR estimates of exacerbation of chronic disease (e.g., work-aggravated asthma)
may also need to take causation into account so that the burden of disease is not
underestimated [47].
Beyond this, use of the PAR as a measure of risk itself has been questioned. It is
important to remember that a basic assumption is that the relative risk upon which
the PAR is based must accurately reflect exposure effects in the target population
[3, 48]. Another assumption is that the dichotomous classification of exposure into
two levels, exposed and unexposed, yields an unbiased estimate of the PAF when
there is non-differential misclassification of exposure, an assumption that has been
challenged [49].
Finally, the burden of disease, which the PAR attempts to capture, may transcend
simplistic notions of the presence or absence of a diagnosis. One alternative measure of burden is ‘disability adjusted life years’ (DALYS). To apply this to a specific
health condition, such as occupationally related asthma, requires an assumption of
the proportional risk. In other words, the PAR as conceptualized above is intrinsically linked to such an exercise. For example, Driscoll et al. [50] presumed an
occupational PAF of 21% to estimate a global burden of occupationally associated
asthma DALYS of 1 621 000.
Beyond DALYS, which address disability, other manifestations of the burden
of disease, such as impaired quality of life and economic disadvantage, are by no
means trivial. This points the way to future research, which needs to address this
knowledge gap in the field of work-related asthma. In the meantime, the consistency
of the PAR data that we do have certainly underscores the importance of workplace
factors in the overall burden of asthma.
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Definition and diagnosis of occupational asthma
André Cartier
University of Montreal, Department of Medicine, Hôpital du Sacré-Coeur de Montréal,
5400 Boul. Gouin Ouest, Montréal, Canada
Abstract
Occupational asthma is a disease characterized by variable airflow limitation and/or hyperresponsiveness and/or inflammation due to causes and conditions attributable to a particular occupational environment and not to stimuli encountered outside the workplace. Two types of occupational
asthma are distinguished based on their appearance after a latency period or not: the classical
occupational asthma requiring a period of sensitization and irritant-induced asthma occurring after
acute exposure to high concentrations of irritants. The diagnosis of occupational asthma should
be based on objective means and cannot rely only on history (which is, although very sensitive,
not sufficiently specific) or even on confirming the presence of asthma with positive skin tests to
the relevant allergen/agent found at work. Inquiring about direct or indirect exposure to known
sensitizers should be part of the questionnaire of any adult with new onset asthma. Monitoring
of peak expiratory flows at and off work is a useful tool but may not be sufficiently sensitive or
specific; combining it with monitoring of the provocative concentration of methacoline inducing
a 20% fall in FEV1 and possibly sputum induction may improve the accuracy of the diagnosis.
Specific inhalation challenges in the laboratory or in the workplace are the reference standard for
confirming the diagnosis of occupational asthma. They are safe when done under the close supervision of an expert physician by trained personnel. Any new case of occupational asthma should be
considered as a sentinel event.
Definitions
Work-related asthma refers to asthma symptoms worsened at work. It includes
asthma exacerbated at work, discussed in the next chapter, and occupational asthma
(OA). Various definitions have been given to OA. The one proposed by Bernstein et
al. [1] encompasses most of them: “Occupational asthma is a disease characterized
by variable airflow limitation and/or hyperresponsiveness and/or inflammation due
to causes and conditions attributable to a particular occupational environment and
not to stimuli encountered outside the workplace”. Two elements in this definition
are important. The agent (identified or not) should be specific to the workplace and
be causally related to the disease. Relevant agents are airborne dusts, gases, vapors
Occupational Asthma, edited by Torben Sigsgaard and Dick Heederik
© 2010 Birkhäuser / Springer Basel
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André Cartier
or fumes [2]. This definition thus excludes asthma triggered by irritant mechanisms
such as cold air or exercise. A previous history of asthma does not exclude the diagnosis of OA. Two types of OA are distinguished based on their appearance after
a latency period or not. The most frequent type, which is usually quoted as OA,
appears after a latency period leading to sensitization (either allergic as for most
high- and certain low-molecular-weight agents or through unknown mechanisms).
The other category does not require a latency period and includes irritant-induced
asthma or reactive airways dysfunction syndrome (RADS), which may occur after
single or multiple exposures to high concentrations of nonspecific irritants [3, 4]
and is discussed in another chapter.
Investigation
As opposed to the traditional pneumoconiosis where the diagnosis is only based
on exposure history and chest radiograph abnormalities, OA can be and should
be confirmed by objective means. Indeed, the social consequences of making or
refuting such a diagnosis are important for both the worker and its employer [5–7].
In order to prevent further deterioration of asthma, it is essential to withdraw the
worker from exposure to the offending agent [8, 9]: this imposes a serious stress to
the worker and his family and may mean loss of job or benefits or even moving to
another town. On the other hand, removing a worker who does not have OA from
exposure has the same consequences, whereas adequate environmental control (e.g.,
reduction of exposure to irritants) and better control of asthma may be sufficient to
allow the worker to continue his job without loss of income.
The different steps involved in the investigation of OA are: history, pulmonary
function tests, immunological tests, combined monitoring of peak expiratory flows
(PEF), non-allergic bronchial responsiveness (NABR) and sputum induction, and
specific bronchial challenges. Although specific inhalation challenges are considered the reference standard, all steps involved in the investigation have their own
usefulness and they all add up to make the diagnosis, with combination of various
elements strengthening its likelihood.
The purpose of this chapter is to review the different steps involved in the investigation of OA with a latency period.
History
The questionnaire is the basic, essential tool used in most epidemiological surveys
and all individual assessments.
The classical history of OA is one of a worker whose asthma is worse at work,
improving over weekends or holidays. However, this pattern is often absent as
72
Definition and diagnosis of occupational asthma
symptoms are also usually present outside the workplace, being triggered by exposure to irritants such as cold air, fumes or upon exercise. Furthermore, the process
involved may be in use irregularly or the worker may be unaware that a specific
process is involved as he is not involved directly with it. In many cases, symptoms
are even more severe at home, awaking the subject at night, and weekends may not
be long enough to allow recuperation. Finally, even workers without work-related
asthma regularly report improvement of asthma during weekends and holidays, in
41% and 54% of cases, respectively [10]. A previous history of asthma may also
postpone the diagnosis. Symptoms may develop after only a few weeks or after
several years, duration of exposure tending to be shorter for low-molecular-weight
chemicals [11].
The concomitant occurrence of rhino-conjunctivitis at work, especially in a
worker exposed to high-molecular-weight chemicals who develops asthma is surely
suggestive of OA [12]. Although rhinitis is as frequent with low- and high-molecular-weight agents, symptoms are usually more severe with the latter [12]. It often
precedes or coincides with the development of OA, especially with high-molecularweight chemicals [12]. Rash (urticaria or contact dermatitis) is sometimes associated
with OA, usually on exposed surfaces (droplets) or by direct contact (e.g., latex
gloves).
However, a history suggestive of OA, even in a worker exposed to a known
sensitizer, is not sufficient to make the diagnosis: questionnaires are sensitive but
not specific tools. Indeed, even in the hands of expert physicians, we showed in
a prospective study of 162 workers referred for OA that the predictive value of
a positive questionnaire was only 63%, while the predictive value of a negative
questionnaire was 83% [13]. Therefore, in more than one third of cases, objective
testing showed that the subjects did not have OA, although the initial questionnaire
had been suggestive.
Pulmonary function tests and diagnosis of asthma
To make the diagnosis of OA, one must first confirm the diagnosis of asthma.
Although the latter can be confirmed by the presence of reversible airflow obstruction, e.g., increase of FEV1 greater than 12–15% after a beta-2 agonist, most workers investigated for OA have normal spirometry when seen in the clinic. Furthermore, pre- and post-shift monitoring of FEV1 has not proven sensitive or specific
enough to be a useful tool in the investigation of OA [14–16].
Increased non-allergic bronchial responsiveness (NABR) is the hallmark of
asthma, but it is also present in other conditions such as rhinitis and chronic
obstructive lung diseases. Therefore, alone, the presence of increased NABR does
not make the diagnosis of OA. It may suggest that the subject has OA, common
asthma, or one or other of the conditions listed above. There is a need for further
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André Cartier
confirmation of work-related asthma. However, the absence of increased NABR as
assessed shortly (minutes, hours) after a work shift in a worker who complains of
symptoms virtually excludes OA [17], although, in rare instances, specific inhalation challenges have been positive in workers without increased NABR [18, 19].
Even in the presence of OA, NABR may be normal in a worker who has left work
for several days (a weekend may be enough [20]) or weeks/months. Return to work
or even a specific inhalation test will then increase the bronchial responsiveness in
the asthmatic range [21, 22].
Work visit
It is essential to obtain a list of the different agents used at work by the subject but
also by colleagues, as the exposure may be indirect, and to find out if other workers
have respiratory complaints. This can be done by asking the employer directly or
the local health department for the material safety data sheets (MSDS) for the different products used in the plant. Unfortunately, these MSDS are often incomplete,
lacking information on sensitizing chemicals found in small amounts that may be
enough to trigger asthma [23].
Immunological testing
The presence of immediate skin reactivity or increased specific IgE or IgG antibodies
may reflect sensitization and/or exposure to a suspected agent but it does not imply
that the target organ (the bronchi in this instance) is involved. This has been shown
for common allergens and occupational sensitizers such as snow crab [15, 24] and
isocyanates [25]. These tests are, however, useful as they can support the diagnosis
and may help to identify which agent mat be relevant. The problem is the lack of
standardization for most allergens.
With most high-molecular-weight chemicals for which good extracts are available, such as cereals or psyllium, negative skin tests to these allergens cannot entirely
exclude the diagnosis of OA but make it very unlikely. Indeed, the worker may still
be sensitized to another agent found in the workplace or to another component of
the offending agent. Conversely, a positive skin test does not confirm the diagnosis, as its predictive positive value is low. For example, in a study by Bardy et al.
[15] the positive and negative predictive values of skin tests/radioallergosorbent
test (RAST) to psyllium were 22/16% and 100/100%, respectively. In snow crabworkers’ asthma, the odds for the presence of OA in a subject with positive skin
tests to snow crab extract or RAST ratio > 4.5 were respectively 69% and 79%,
whereas the odds for the absence of OA in a subject with negative skin test or RAST
ratio < 4.5 were 76% and 73%, respectively [24]. With most low-molecular-weight
74
Definition and diagnosis of occupational asthma
chemicals, skin tests or specific IgE or IgG are either unavailable or not sufficiently
sensitive or specific to refute or to make the diagnosis of OA. Other in vitro tests
such as basophil histamine release or assay of monocyte chemoattractant protein-1
by peripheral blood mononuclear cells [26] may offer higher sensitivity or specificity
but again they do not confirm the diagnosis of OA.
Even if specific inhalation challenges are considered the reference test, they are
not always available, and combining various tests may increase the likelihood of a
correct diagnosis. In the case of high-molecular-weight agents, combining a history
highly suggestive of OA with a positive methacholine challenge and a positive skin
test to a high-molecular-weight agent gives a post-test probability of > 90% of disease and may be enough. On the other hand, negative combined tests results do not
appear to provide clinicians with sufficient certainty to rule out OA [27].
Monitoring of PEF and NABR and sputum cell counts
The availability of portable, inexpensive devices has allowed physicians to monitor PEF at work and off-work. This approach was first used in the investigation of
work-related asthma by S. Burge and colleagues [28, 29]. Coupling PEF monitoring and changes in NABR for periods at work and away from work has also been
proposed [30–32] (Fig. 1). Recently, monitoring of eosinophils in sputum induction
has also been proposed [33, 34] as a useful tool. The usefulness of PEF monitoring
in diagnosing OA has been reviewed in various consensus reports [7, 35–37].
When compared to specific inhalation challenges as the reference, PEF monitoring has a sensitivity of around 64% and a specificity of 77%. Malo et al. [38]
showed that sensitivity and specificity of PEF monitoring was optimal when PEF
were measured every 2 hours at work and off-work. Observing the deterioration
of asthma while at work is still the best way to evaluate changes in PEF [32, 39].
A computer-based system analysis of PEF has been developed by Gannon and colleagues and validated as a useful tool to assess work-related changes in PEF [40–42].
It is, however, sometimes difficult to distinguish between work-exacerbated asthma
and OA, even by experts [43]. The poor sensitivity or specificity of PEF monitoring
in certain subjects as compared to specific bronchial challenges can be explained
by several means. Indeed, even if performed under close supervision of a technician, PEF may greatly underestimate or overestimate changes in airway caliber as
assessed by FEV1 [44–46]. Furthermore, PEF are effort dependent and thus require
collaboration of the worker, which is not always obtained due to fear of loosing his
job or malingering in order to get some compensation benefit. When PEF data are
stored on a computer chip and subjects are unaware of this, two studies [47, 48]
have shown that many workers will falsify their records as around 50% of values
are inaccurately reported on diaries either in terms of the recorded value or of the
timing of the measurement or as fabricated results.
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André Cartier
Figure 1.
Monitoring of PEF (PEFR; upper panel) and PC20-histamine (lower panel) in a crab processing
worker. Before returning to work, the subject was asymptomatic with borderline PC20. Upon
return to work, as illustrated by the black squares, the subject had a recurrence of asthma
symptoms requiring rescue salbutamol (illustrated by the losanges) with significant changes
in PEF and a significant fall in PC20. Work withdrawal was associated with return to baseline
of PEF and gradual, although very slow, recovery of PC20 over 1 year. This confirmed the
diagnosis of occupational asthma. Reproduced with permission from [59].
The minimum period of monitoring should be at least 2 weeks at work and
off-work to be able to draw some conclusions. In certain situations, particularly
when asthma is severe or when the nature of the offending agent is unknown and
intermittent, the interpretation of the monitoring may be difficult [32]. Subjects
should be asked to take their beta-2 agonists on demand only, but should continue
their inhaled steroids regularly. Indeed, reduction of inhaled steroids upon return to
work may be associated with deterioration of asthma and reduction in PEF, which
may be mistaken as diagnostic of OA. We usually avoid long-acting beta-2 agonists
and leukotrienes antagonists, but allow the use of theophylline at the same dosage throughout the entire monitoring. In severe asthmatics, it may be necessary to
withdraw the subject from work until his asthma is under control and on minimum
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Definition and diagnosis of occupational asthma
treatment before returning him to work; deterioration of asthma may then suggest
that asthma is caused by work.
The association of NABR monitoring to PEF monitoring at work and off-work is
now frequently used in the investigation of OA [30–32]. NABR can be assessed by
several means, but methacholine and histamine inhalation challenges with determination of the provocative concentration inducing a 20% fall in FEV1 (PC20) are the most
reliable and are well standardized. Indeed, whereas exposure to irritants does not
induce marked and prolonged changes in NABR, OA may be associated with significant and often long-lasting changes in NABR. However, Côté et al. [31] and Perrin et
al. [32] showed that PC20 monitoring at and off-work did not improve the sensitivity
or specificity of PEF monitoring in diagnosing OA. We recommend that monitoring of
PEF is coupled to monitoring of NABR: indeed, when changes in PEF are associated
with parallel changes in NABR, the diagnosis of OA is highly probable. If the monitoring of PEF and NABR are discordant, further investigations should be completed,
such as specific bronchial challenges in the workplace or in the laboratory. When the
monitoring of PEF and NABR shows no evidence of asthma in a symptomatic subject
while at work, this is enough to exclude the diagnosis of OA.
As sputum eosinophils may increase following return to work in subjects with
OA [33, 34, 49], we are regularly adding this parameter in our evaluation of workers. However, we tend to use a positive result as potentially indicating OA rather
than confirming it; when there is a discrepancy between monitoring of PEF, NABR
or sputum eosinophils, we tend to complete our investigation with specific inhalation challenges. In the absence of increased NABR and changes in airway caliber, an
increased count of sputum eosinophils at work in a worker symptomatic of cough
may suggest the diagnosis of eosinophilic occupational bronchitis [50, 51]. Unfortunately, monitoring of sputum induction is available in only a few centers and is
of limited value. Finally, there is still no evidence that monitoring of exhaled NO is
useful in the investigation of OA but this merits further investigation.
Although monitoring of PEF and NABR are useful tools, they are time consuming, require the subject’s collaboration and may be hazardous in workers giving a
history of severe asthma at work as exposure may not be titrated as easily as when
the challenge is done in the laboratory. They are particularly useful as a screening
procedure when the worker is exposed to several sensitizers or when the offending
agent is unknown.
Specific inhalation challenges
Specific inhalation challenges (SIC) are still considered the reference test to confirm the diagnosis of OA [52–56]. Originally done in the laboratory and aiming
at mimicking work exposure [57], they are now frequently done in the workplace
[58, 59].
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SIC are safe when performed under the close supervision of an expert physician
and with trained personnel and are thus limited to specialized centers. Resuscitative measures should be available. When performed in the laboratory, the exposure
chambers should be well ventilated and isolated to minimize exposure to the personnel. The tests can be carried out on an outpatient basis. Most challenges are done
in an open fashion, the subject knowing the nature of the exposure. This is inevitable for workplace challenges but when challenges are done in the laboratory, we
sometimes blind the exposure if we suspect that the subject is mimicking symptoms
(particularly cough).
Although there is no standardized protocol, the methodology is well developed
[52, 55, 56].
Drugs should be withheld before specific bronchial challenges according to standard recommendations [55] as with methacholine challenges [60]. Beta-2 agonist
(oral and inhaled), inhaled ipratropium bromide and cromoglycate must be withheld for 8 hours. Inhaled long-acting beta-2 agonists, tiotropium and nedocromil,
and leukotrienes antagonists should be discontinued for 48 hours. In most subjects,
long-acting theophylline should be withheld for 48 hours (or 72 hours for once-aday tablets), but may have to be continued in subjects who show too much variability in their spirometry throughout the day when they are withheld. If it is used,
there should be daily serum monitoring to ensure a uniform effect. Inhaled (and
occasionally oral) corticosteroids should be continued at their minimal dosage to
keep asthma under control, but taken only in the evening of each challenge day at
the same total dose. Although the dose of the agent required to induce a bronchial
reaction may indeed be increased by theophylline or corticosteroids, these drugs
would not abolish the response if the subject is sensitized.
While FEV1 is the standard parameter used to assess changes in airway caliber,
PEF are not reliable enough particularly in the late bronchial response as they may
underestimate or overestimate changes [44]. While some investigators favor the
use of airway resistance (Raw), most consider that it is less reliable than FEV1. In
addition, we routinely measure lung volumes on the control day (total lung capacity, residual volume and functional residual capacity) to be able to confirm airways
obstruction, as indicated by airway trapping and hyperinflation, during exposure
to the offending agents in cases where simple spirometry is dubious (e.g., poor
collaboration of the subject).
In all cases, spirometry should be monitored on a control day to ensure stability
of airway caliber; in more severe asthmatics, the subject is first observed for at least
8 hours on a non-exposed day, whereas most subjects can be exposed on the first
day to a control irritant, e.g., lactose powder, paint diluent, resin, etc., presented in
the same way as the suspected agent [52, 55]. FEV1 is monitored at baseline every
10 minutes for 1 hour, every 30 minutes for 1 hour, and then hourly for at least
8 hours after the end of exposure. If the subject show too much variability of his
FEV1 (> 10%) during this control day or if the FEV1 is too low (we usually require
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Definition and diagnosis of occupational asthma
an FEV1 > 2.0 L or at least > 1.5 L and > 70% of predicted), the tests should be
postponed and asthma controlled by adjusting the medication. At the end of the
control day, a methacholine challenge test followed by sputum induction are done
to determine the level of NABR as assessed by the PC20 dose and the profile of
airway inflammation. The PC20 may help us determine the starting concentration
to the offending agent on the next day, the lower the PC20, the lower the exposure.
In cases where allergic alveolitis is also suspected, monitoring of carbon monoxide
lung diffusion capacity is measured on control and subsequent days in the morning
and late afternoon, as well as monitoring of white blood cell counts.
Challenges preformed in the laboratory
When performed in the laboratory, specific bronchial challenges can be done in
several ways, depending on the nature of the agent, i.e., powder, aerosol, liquid or
gas. With powders, like flour, psyllium or red cedar, the subject may be exposed to
a fine dust, mimicking work exposure by pouring the dust from one tray to another
[57] or using a dust generator [61–63], which allows proper monitoring, regulation
of exposure, establishment of dose-response curves, and reduces the risk of severe
and/or irritant reactions. The agent may be diluted initially with an inert agent such
as lactose to avoid severe reactions. Alternatively, the worker may be exposed to an
aerosol of a crude extract. Exposure to non-powder agents is usually done by reproducing work environment, e.g., by nebulizing an aerosol of the isocyanates hardener
or by having the worker breath over a bottle of methacrylate glue. Isocyanates and
other gases can be generated in their gaseous form in a closed circuit generating
chamber [64, 65] or a whole-body exposure chamber [66, 67]. Whenever possible,
the level of exposure should be monitored to avoid high exposure and therefore
irritant reactions.
Baseline spirometry on each exposure day should be reproducible, i.e., <10%
of the control day. The exposure should be progressive (1 breath, 10–15 seconds,
1 minute, 2 minutes, 5 minutes, etc.). The total duration of exposure is a function of
the type of agent and the history given by the subject. The dose may be conveniently
increased sequentially by serial increases of the exposure period, and/or increasing
the concentration of the agent. For high-molecular-weight chemicals for which positive skin tests can be elicited, exposure is increased progressively for up to 2 hours
with in-between functional assessments, unless the subject gives a history suggestive
of an isolated late asthmatic reaction. As on the control day, spirometry is assessed
immediately and 10 minutes after each period of exposure. A significant reaction is
defined as a 20% fall in FEV1. At the end of exposure (whether it is after 2 hours or
once the FEV1 has dropped significantly by 20%), spirometry is performed as on the
control day for up to 8 hours. With low-molecular-weight chemicals such as isocyanates, which are more often associated with isolated late responses [68], exposure
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should be more gradual and over a few days: one breath, 15 seconds, 45 seconds
and 2 minutes on the first day, 30 minutes on the second day and 2 hours on a third
day. However, this pattern of exposure may be modified by reducing the duration
of subsequent exposures if there is a suggestion that the subject is starting to react.
If there is no significant variation in FEV1 on the last exposure day, NABR and sputum induction should be reassessed at the end of that day; if there is no significant
change from baseline, there is no further exposure, whereas, if PC20 is significantly
lower or if there is a significant increase in eosinophils, we repeat the exposure on
the next day for up to 4 hours as the test may then be positive [69], sometimes even
after a shorter exposure.
Tests in the workplace
Tests in the workplace are now done more frequently, especially when the relevant
agent at work is unknown or when there are several potential sensitizing agents.
They are also done in stepwise manner as the subject may experience a significant
fall in FEV1. Spirometry is performed in the same way throughout the day [58, 59].
Exposure to the offending agent is, however, less well controlled and monitored
than in the laboratory, and it may be difficult to ensure that the subject is really
exposed to the relevant agent at work. This may be, however, the only way to confirm the diagnosis of OA especially in cases where the nature of the offending agent
is unknown.
Interpretation of the tests
A significant reaction is defined as a 20% fall in FEV1. Typical patterns of bronchial reactions have been described [57, 68] (Fig. 2a). Immediate reactions are
maximal between 10 and 30 minutes after exposure with complete recovery within
1–2 hours; although usually readily reversible by inhaled beta-2 agonists, they are
actually the most dangerous as they can be severe and unpredictable, particularly
in subjects for whom skin tests with the suspecting agent are not possible, stressing
the importance of progressive exposure. Late reactions develop slowly and progressively either 1–2 hours (early late) or 4–8 hours (late) after exposure; they may
occasionally be accompanied by fever and general malaise but extrinsic alveolitis
should then be considered. Contrary to popular belief, they generally respond well
to inhaled beta-2 agonist, although the response may be of shorter duration in some
subjects [70]. Dual reactions are a combination of early and late. A recurrent nocturnal asthma pattern has also been described and is likely related to an increase in
NABR following exposure [71].
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Definition and diagnosis of occupational asthma
a
b
Figure 2.
Patterns of typical (a) and atypical (b) bronchial responses to specific inhalation challenges.
Each point represents the mean % change in FEV1 (n = number of subjects in each group) at
several time points following the last inhalation of the responsible agent during a specific
inhalation challenge. Reproduced with permission from [68].
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Atypical patterns (Fig. 2b) have also been described with isocyanates and other
low- or high-molecular-weight chemicals: they include the progressive type (starting
within minutes after end of exposure and progressing over the next 7–8 hours), the
square-waved reaction (with no recovery between the immediate and late components of the reaction) and finally the prolonged immediate type with slow recovery.
Low-molecular-weight chemicals are more often associated with atypical patterns
as compared to high-molecular-weight chemicals.
Irritant reactions are not well characterized but falls in FEV1 that recover rapidly
within 10 or 20 minutes are suggestive of an irritant pattern. It may be impossible to
interpret results of specific bronchial challenges in subject with too much variability
of FEV1, stressing the importance of an adequate control day.
A positive test confirms the diagnosis of OA, whereas a negative test in the
workplace, or in the laboratory, does not absolutely rule out the diagnosis of OA
in a worker who has not been exposed to work for several months, as he may have
become “desensitized” [22, 59, 69]; this is particularly true if there is a change in
PC20 following the specific challenges [22, 69]. The worker should be returned to
work with monitoring of PEF and bronchial responsiveness for at least a few weeks
before excluding the diagnosis. False negative challenges in the laboratory may also
be due to exposure to the wrong agent or administration of a forbidden drug (such
as an inhaled beta-2 agonist) before the test. However, if the subject had his/her
symptoms during the challenge procedure without any change in spirometry, these
tests are conclusive and exclude the diagnosis of OA.
Conclusion
The diagnosis of OA should be based on objective means and cannot rely only
on history or even on confirming the presence of asthma and positive skin tests.
Monitoring of PEF, PC20 and sputum induction are useful tools but may not be sufficiently sensitive or specific. Specific inhalation challenges in the laboratory or in
the workplace are the reference standard for confirming the diagnosis of OA, but
should be done under the supervision of expert physicians.
Unanswered questions
-
82
What is the role of exhaled NO in the investigation of OA?
There is a need for a better characterization of the bronchial response to irritants
by using indices such as NABR, sputum induction or exhaled NO.
Duration of exposure to the agent in the laboratory needs to be better standardized. How long should the exposure be before we consider a challenge to be
negative, 2, 4 hours?
Definition and diagnosis of occupational asthma
-
Monitoring the exposure is not always possible and this is clearly a limit of specific inhalation challenges as it may be sometimes difficult to exclude an irritant
effect. There is thus a need to improve our capacity to do such monitoring.
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in non- allergic bronchial responsiveness. Clin Allergy 14: 61–68
87
Work-exacerbated asthma
Paul K. Henneberger1 and Carrie A. Redlich2
1
National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, MS H2800, 1095 Willowdale Road, Morgantown, WV 26505, USA
2
Occupational and Environmental Medicine and Pulmonary & Critical Care Medicine, Yale
University School of Medicine, 135 College Street, New Haven, CT 06510, USA
The findings and conclusions in this report are those of the author and do not necessarily
represent the views of the National Institute for Occupational Safety and Health.
Abstract
Exposures at work can contribute to both the onset and exacerbation of asthma. This chapter
summarizes key information regarding work-exacerbated asthma (WEA), a common condition
that has received little attention compared to new occupational asthma. WEA refers to pre-existing
or concurrent asthma that is worsened by factors at work. WEA, as with asthma in general, is
heterogeneous, with multiple phenotypes and triggers. The prevalence of WEA has ranged from
about 15% to over 50% among working adults with asthma in published studies, but is rarely
diagnosed by clinicians. WEA occurs in a wide range of industries and occupations, including education, services, manufacturing and construction, and can lead to job changes and unemployment.
Multiple factors at work can exacerbate asthma, including various irritants, allergens, molds,
cold and exertion. Cleaning products and building renovation in non-industrial workplaces such
as schools and offices are commonly implicated. WEA can lead to substantial adverse outcomes,
similar to OA. Management of WEA should focus on reducing work exposures and optimizing
standard medical management.
Introduction and definitions
Asthma is a common disease, affecting up to approximately 15% of working-age
adults [1]. Work-related asthma (WRA) comprises both occupational asthma (OA)
in which exposures at work cause new onset asthma, and work-exacerbated asthma
(WEA) in which existing asthma is aggravated by conditions at work. An estimated
15% of new adult onset asthma is attributable to exposure to sensitizers or irritants
in the work environment [2, 3]. The literature on WRA has focused primarily on
sensitizer-induced OA. Asthma exacerbations are common, and can be triggered by
a number of factors, including workplace exposures. However, WEA has received
less attention than OA. The purpose of this chapter is to summarize relevant
Occupational Asthma, edited by Torben Sigsgaard and Dick Heederik
© 2010 Birkhäuser / Springer Basel
89
Paul K. Henneberger and Carrie A. Redlich
information about WEA, including the definition and epidemiology of WEA, causative factors, natural history, and a suggested clinical approach for diagnosis and
management of WEA.
WEA refers to pre-existing or concurrent asthma that is worsened by workrelated factors [3]. A case of ‘concurrent asthma’ has onset while the individual
is employed, but the onset is not attributable to work. As with asthma in general,
definitions of WEA have varied depending on the clinical, research, or public health
setting, but all depend on defining “asthma” and “asthma exacerbation”. This
can be challenging, given that asthma is a heterogeneous syndrome that involves
multiple phenotypes, multiple factors can exacerbate asthma, and that exacerbations can vary from brief worsening of symptoms to severe episodes requiring
hospitalization or resulting in death. Key features of asthma include airway inflammation, airway hyperresponsiveness (reversible airflow obstruction), and recurrent
symptoms of wheezing, chest tightness or cough [4, 5]. Clinical studies are more
likely to use objective tests such as reversible airflow obstruction on spirometry and
medication usage to define asthma. Epidemiological studies are more likely to use
self-reports of doctor-diagnosed asthma and asthma symptoms. Work-relatedness
is primarily assessed by self-reports of symptoms or medication use relative to
work, or occasionally by physiologic indicators such as work-related changes in
peak flow rates.
Prevalence of WEA
The prevalence of WEA has been investigated using several approaches. A relatively small but growing number of studies have evaluated the frequency of WEA
in general populations of asthmatics and provide estimates of the prevalence of
WEA among adult asthmatics (Tab. 1) [6–14]. The prevalence of WEA estimated
from these studies was quite variable, as shown in Table 1, ranging from 14% to
38% among all adults with asthma, and from 14% to over 50% among working
adults with asthma, a more appropriate at risk group (denominator). The populations studied, age ranges, asthma definitions, geographic locales, and criteria for
work exacerbation vary in these studies, as noted in Table 1. Asthma was defined
as doctor-diagnosed asthma in most studies, with access to medical records to identify cases, except for studies that selected participants from the general population.
Work exacerbation was generally based on self-reported asthma symptoms that had
worsened in relation to work, typically within the past year; however, these reports
rarely included the frequency or severity of exacerbation.
The frequency of WEA has also been expressed as a percentage of all WRA
cases, with a denominator that includes both OA and WEA cases (Tab. 2) [15–26].
Most of these studies were conducted in clinical referral settings or relied on surveillance or worker compensation systems for identifying cases of WRA. Estimates
90
G Pop
G Pop
HMO
Clinics
HMO
G Pop
HMO
Primary
care
NHI
system
Abramson
1995 [6]
Blanc
1999 [7]
Bolen
2007 [8]
Goh
1994 [9]
Henneberger
2002 [12]
Henneberger
2003 [10]
Henneberger
2006 [11]
Mancuso
2003 [13]
Saarinen
2003 [14]
969
OA excluded
102
all employed
598
OA excluded
42
28 employed
1,461
802
95
all employed
160
159
No. of asthma
cases
20–65,
43 mean
39 mean
18–44
18–65,
42 mean
18–44
20–54
18–44,
34 mean
20–44
43 mean
Age (years)
Asthma symptoms caused or worsened by
work at least weekly in past month
At least one of several job conditions makes
asthma worse
Relevant exposure and work-related pattern of
symptoms or medication use
Coughing or wheezing is worse at work than
when not at work
Current work environment makes asthma
worse
Work environment is asthma trigger
Pattern of serial peak expiratory flow rate
consistent with WEA
Report chest tightness at work
Respiratory symptoms at work
Criteria for WEA (self-reported on
questionnaire unless indicated otherwise)
NA
NA
23%
14%
25%
27%
NA
38%
20%
All adults
with asthma
§
20%
58%
24%
21%
NA
NA
14%
NA
NA§
Working adults
with asthma
Prevalence of WEA among
* Abbreviations for setting: G Pop, general population; HMO, health maintenance organization; NHI, national health insurance
NA, not applicable
Setting*
Reference
Table 1. Prevalence of WEA among adults with asthma (selected studies)
Work-exacerbated asthma
91
92
SENSOR Criteria
Asthma worse at work, with or without prior
asthma, no sensitizer exposure. Objective testing
common
Work-related sx, irritants or other aggravating factors,
no sensitizer exposure. Objective testing common
SENSOR Criteria
Asthma sx temporally related to work exposure and
negative SIC
Aggravation of asthma sx at work, negative SIC
SENSOR Criteria
SENSOR Criteria
SENSOR Criteria
SENSOR Criteria
Pre-existing asthma, and cleaning-related sx
Pre-existing asthma worsened by exposure at work
Criteria for WEA†
20%
50%
49%
51
41%
23%
35%
19%,
45%
14%
45%
58%
36%
% with
WEA
236
469
351
305
444
1101
157
454
301
26
81
No. with
WRA
* Abbreviations Clinical Setting: OHC system, occupational health clinic; Referral clinic, clinic for suspected work-related asthma;
Worker compensation, data from worker compensation system.
†
Abbreviations for Criteria WEA: rx, medications; sx, symptoms; SIC, specific inhalation challenge
§
A subset of subjects reported in [9]. SENSOR, Sentinel Event Notification Systems for Occupational Risks. Data from CA, MA, MI,
NJ, unless otherwise specified.
SENSOR criteria WEA, asthma in 2 years before new occupational setting, asthma symptoms work-related, more asthma symptoms
or medications in new setting
Asthma clinic
Adults
41 median
18–65+
Mean 46
Goe 2004§ [19]
Larbanois 2002 [20]
Tarlo 2000 [25]
SENSOR surveillance
Referral clinic
Fletcher 2006 [18]
43 median
37 mean F,
34 mean M
20–60,
43 mean
18–70+
32–54
18–70+
Mean ~40
OHC (NY)
Curwick 2006 [16]
de Fatima 2007 [17]
23–25
Age (years)
Referral clinic
SENSOR cases in health care
Survey of physician first reports
(CA)
Rosenman 2003§ [24] SENSOR cases cleaning products
Tarlo 1995 [26]
Worker compensation
1922 subjects selected from
birth cohort
Workers compensation (WA)
Cleaners
Caldeira 2006 [15]
Lemiere 2007 [21]
Pechter 2005§ [22]
Reinisch 2001§ [23]
Clinical setting*
Reference
Table 2. Prevalence of WEA among all work-related asthma (WRA) cases (selected studies)
Paul K. Henneberger and Carrie A. Redlich
Work-exacerbated asthma
of prevalence of WEA as a percentage of all WRA cases ranged from 14% to over
50%, as shown in Table 2. These estimates were highly dependent on factors such
as physician recognition, referral patterns, reporting system, and local workers
compensation laws. WEA typically is not diagnosed by clinicians in settings where
it is not clearly recognized as a condition under worker’s compensation rules, such
as in New York State and many other states in the United States [18]. Where WEA
is recognized, as in the Canadian province of Ontario, or more recently in the
province of Quebec, the number of cases of WEA compared to OA tends to rise
[21, 25, 26].
The prevalence of WEA has also been described in selected groups of asthmatic
workers, such as office workers, cleaners, or construction workers (Tab. 3), with up
to 70% of asthmatics reporting exacerbation of their asthmatic symptoms related to
their work [17, 27–32]. As with the other clinical and epidemiological studies, the
worker populations and diagnostic criteria were variable.
Exposures and WEA
As with non-work-related asthma, a number of diverse exposures and factors have
been associated with WEA (Tab. 4). Overall, most commonly reported are various
irritant mixed exposures, such as dusts, second-hand smoke, solvents, cleaning
products, and fumes at work [9, 18, 25–27]. Common allergens and molds, frequently in settings with inadequate indoor air quality such as office buildings and
schools, have also been reported as triggers for asthma symptoms [3, 18, 28]. In
addition, non-chemical conditions can also exacerbate asthma at work, including
extremes of temperature, physical exertion, emotional stress, and viral infections [3,
11, 14, 25–27, 33].
There are few quantitative data regarding the levels of work exposures that
trigger asthma, and comparisons between studies and with different definitions
or criteria for WRA can be difficult. However, together these studies indicate that
exposures associated with WEA, as compared to new onset OA, were less likely to
be specific sensitizing agents, and more likely to be irritant exposures [3, 9, 25]. The
irritants associated with WEA typically occur at lower levels than those reported to
cause new onset irritant-induced OA [3].
WEA has been reported in a wide range of industries and occupations, including public administration, wholesale and retail trade, cleaning, manufacturing,
education, and construction [7, 9, 12, 14, 27]. Several studies have suggested
a healthy worker effect, where asthmatic workers leave workplaces with more
asthma triggers [10, 12, 34]. Although the specific asthma triggers can be difficult
to identify, it is clear that WEA can occur in numerous different work settings,
including non-industrial workplaces such as office buildings, schools, and laboratories.
93
94
Type of workers/
work setting
Low income inner
city patients
Office workers
Cleaners
Soldiers in Iraq
Swimming pool
workers
Cosmetic workers
Construction
workers
Reference
Berger
2006 [27]
Cox-Ganser
2005 [28]
De Fatima
2007 [17]
Gouge
1994 [29]
Jacobs
2007 [30]
Kreiss
2006 [31]
Sauni
2001 [32]
18–64
42 mean
16–65
40.5 mean
21–44
37 mean F
34 mean M
46 mean
18–55
Age (years)
10
39
67
301
Number asthmatics
Symptoms worse at work or
occupational dust cause symptoms
Report asthma worse with
workplace exposure or activities
76
175
108 pre/67 post hire
In last 1 year more asthma attacks 624 working at
and asthma medications, compared pools (number with
to Dutch population
asthma unclear)
Exacerbation of asthma symptoms
Cleaning-related asthma symptoms
Work-related asthma symptoms in
water-damaged building
Asthma worse at current or most
recent job (janitors, security
guards, clerks, restaurant workers,
textile workers)
Criteria for WEA (self-reported
on questionnaire unless indicated
otherwise)
Table 3. Prevalence of WEA among selected asthmatics in certain jobs or work settings (selected studies)
68% worse at work,
66% dust causes symptoms
28% pre-hire asthmatics
58% post-hire asthmatics
OR = 2.6 asthma attack
p < 0.05
70%
38% (46% females/
18% males)
34%
51%
Prevalence WEA among
asthmatics
Paul K. Henneberger and Carrie A. Redlich
Work-exacerbated asthma
Table 4. Selected industries, jobs and exposures associated with WEA
Selected industries / Jobs associated with WEA
Technical, sales and administrative support
Public administration, teaching
Laboratory and medical technicians
Cleaners, janitors
Manufacturing (textile workers, operators, laborers)
Selected exposures associated with WEA
Second-hand smoke
Dusts
Smoke, welding fumes
Chemicals (cleaning products, paints, solvents, acids, ammonia)
Common allergens / molds
Abnormal temperatures
Physically strenuous work
Viral respiratory infections
WEA should also be considered in the context of non-work-related asthma
exacerbations, which are common, and quite variable in severity, time course and
etiology. A number of factors and/or triggers can exacerbate asthma, including viral
infections, allergens, irritants, non-compliance with medications, exercise, stress, or
other medical conditions (e.g., gastroesophageal reflux or sinusitis) [35]. In both
settings many of these exposures are preventable, but in the work setting the patient
typically has less control over the environment.
Clinical characteristics and natural history of WEA
The clinical characteristics and natural history of WEA have received much less
attention than those related to OA. Several studies have now compared clinical
characteristics of patients with WEA to those with OA or to other asthmatics.
The study populations, selection and diagnostic criteria, and other methodological
features have been quite variable, making findings within and between studies difficult to interpret and compare. A limited number of studies comparing WEA and
OA have found predominantly similarities between these groups, including similar
levels of asthma severity, airway hyperresponsiveness, medication usage, and needs
for healthcare [9, 20, 21, 26, 36].
95
Paul K. Henneberger and Carrie A. Redlich
Similarly, the few studies that have evaluated removal from exposure or more
long-term outcomes in WEA have generally found outcomes similar to those for
OA, with persistent asthma but improved symptoms and reduced airway inflammation away from exposure [36, 37], although some differences have also been noted,
such as higher doses of inhaled corticosteroids in WEA [36]. These findings may
reflect selection criteria for the two groups of patients.
A relatively small number of studies have also compared WEA to other asthma
cases. Overall, these studies have tended to find more asthmatic symptoms and/or
more frequent or more severe asthma exacerbations in asthmatics with WEA compared to other asthmatics [11, 14, 21, 38]. However, some of these same studies
have found less severe asthma in WEA using different criteria for asthma severity,
and other studies have found less frequent asthma exacerbations in subjects with
WEA [11, 25].
Socioeconomic impact
Recent studies have begun to evaluate the social and financial consequences of
WEA, comparing WEA to asthma unrelated to work or to occupational asthma
[9, 20, 39]. Again, comparisons within and between studies is difficult, as the studies were based on different patient populations, asthma severities, age ranges, and
diagnostic criteria. Despite these limitations, studies have generally found that WEA
is associated with similar outcomes to those of OA in terms of prolonged unemployment, loss of income, and frequent job changes [9, 20, 39]. However, other studies
have reported less frequent job changes for WEA subjects [9, 20, 26].
Diagnosis, management and prevention of WEA
Clinical studies addressing optimal strategies for diagnosing and managing WEA
are limited, with the great majority of prior studies addressing sensitizer OA. An
expert panel assembled by the American College of Chest Physicians recently published a consensus document on the diagnosis and management of work-related
asthma, including WEA [3]. Relevant conclusions are summarized briefly. WEA
should be considered in any patient with worsening asthma and/or work-related
asthma symptoms. The diagnosis of asthma should be clarified, based on the clinical history, typical symptoms and exam findings, and documentation of reversible
airflow obstruction or airway hyperresponsiveness (e.g., bronchodilator response or
methacholine challenge test), although this can be difficult to demonstrate in some
asthmatics. A careful occupational and medical history is essential. Information on
job exposures, type of industry, ventilation, the onset and timing of symptoms in
96
Work-exacerbated asthma
relationship to work, medication use, symptoms in co-workers, and use of protective equipment should be obtained. History of asthma, childhood asthma, atopy,
rhinitis and sinusitis should also be clarified, with particular focus on the first onset
of asthmatic symptoms, clinical course and triggers.
The relationship between work and asthma exacerbations should be assessed,
most commonly by careful documentation of changes in symptoms and medication use temporally related to work, including specific tasks or jobs at work. More
severe exacerbations may be documented by health care visits or physiological
changes (e.g., in peak expiratory flow rate or forced expiratory volume in one
second). Additional sources of exposure information include Material Safety Data
Sheet (often abbreviated as MSDS), a union, the employer (with patient’s permission), and government agencies. WEA frequently is due to a mixture of substances
rather than a single substance, such as encountered in work settings with several
irritant gases, construction dust from multiple materials, or many types of cleaning
products in use.
WEA should be distinguished from OA, especially if a specific sensitizing agent
is identified at work. This can be challenging if the asthma is longstanding and the
worker is no longer at the suspect job, since chronic asthma tends to respond nonspecifically to multiple triggers. Factors at work and outside work that trigger the
asthma should be identified. Thus allergy testing may be useful in atopic asthmatics.
Data on management and prevention of WEA is also very limited. The goal is
to improve asthmatic symptoms by reducing work triggers and optimizing asthma
treatment. If unsuccessful, a change to a job with fewer triggers may be necessary.
Prevention also focuses on reducing work exposures and factors that can trigger
asthma, and potentially modifying a worker’s job to avoid triggers such as cold
weather.
Summary
WEA refers to pre-existing or concurrent asthma that is worsened by work factors.
WEA is common in both industrial and non-industrial settings, but has received
less attention than OA that is caused by work. A review of the current literature on
WEA demonstrates that the prevalence of WEA among working adults is variable,
ranging from approximately 15% to 50%. Numerous different exposures or conditions at work can exacerbate asthma. WEA clinically shares many features with
OA, including persistent asthma and adverse socioeconomic outcomes (prolonged
unemployment, reduction in income). Management of WEA should focus on reducing work exposures and optimizing standard medical management, with a change
in jobs only if necessary.
97
Paul K. Henneberger and Carrie A. Redlich
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Natural history and prognosis
Dennis Nowak
Institute and Outpatient Clinic for Occupational, Social and Environmental Medicine,
Clinical Centre, Ludwig Maximilian University, Munich, Germany
Abstract
In patients with occupational asthma, the rate of symptomatic recovery after avoidance of exposure to the respective agents is only about one third, worsening with increasing age. Likewise,
persistent nonspecific bronchial hyperresponsiveness at long-term follow-up is found in about
three quarters of these patients. The situation is even worse if patients with occupational asthma
are left in the same workplace. These clinical and functional data are supported by investigations
demonstrating inflammation and airway remodeling in the course of occupational asthma despite
inhaled steroid medication. Given the frequently adverse outcome of occupational asthma, much
more effort should be taken to avoid the disease.
Introduction
The present chapter focuses on factors modifying the onset and the course of occupational asthma (OA) under various conditions. Scientific data in this field are
limited due to various selection processes in a setting in which medical as well as
social, legal and compensational aspects may affect outcomes. Furthermore, small
study sizes, different disease mechanisms, various agents, heterogeneous observation times, and varying treatment schemes contribute to limited consistency and
generalizability. Nevertheless, some practical conclusions can be drawn based on
published evidence.
Onset of disease
In a follow-up of the International Study on Asthma and Allergies in Childhood
(ISAAC) II cohort study in Germany, we demonstrated that, surprisingly, preexisting asthma, allergic rhinitis or atopic dermatitis did not influence job choices of
teenagers [1]. Therefore, reasonable prevention by avoiding specific high-risk jobs
does not seem to occur at least in this population.
Occupational Asthma, edited by Torben Sigsgaard and Dick Heederik
© 2010 Birkhäuser / Springer Basel
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Dennis Nowak
Individual factors and predisposing conditions contributing to an increased risk
for OA due to high- and low-molecular-weight agents are discussed in the respective chapters.
Mainly, the nature of the agent and the intensity of exposure are predictors
regarding the onset of disease. In their frequently cited but – unfortunately – not
renewed review on the natural history of OA, Chan-Yeung and Malo [2] concluded
from the literature on the onset of OA that the majority of patients develop asthma
within the first 1–2 years of exposure, but that new cases can still occur after more
than 10 years of exposure. On average, sensitization to low-molecular-weight
agents seems to require a shorter interval than sensitization to high-molecularweight compounds. Amongst the latter group, workers exposed to laboratory
animal proteins most frequently develop sensitization during the first 2 years of
exposure, but bakers exposed to flour do not, indicating that animal allergens are
much more potent sensitizers than flour [3]. In workers exposed to high-molecularweight agents such as laboratory animal dust, symptoms of rhinitis frequently
precede the onset of asthma symptoms, without this being a general condition, as
shown in a recent follow-up study of bakers’ apprentices [4]. This is less frequent
with exposure to low-molecular weight agents [5–7]. Riu and coworkers [8] demonstrated that the onset of rhinitis was highest among those currently employed in
a high risk job for less than 10 months. Thus, even short exposures, e.g., in holiday jobs, may predispose to occupational rhinitis and indicate an increased risk of
developing OA.
Outcome of patients after cessation of exposure
Recently, Rachiotis and co-workers [9] conducted a systematic review of the
published literature on the symptomatic and functional outcomes of OA after
avoidance of exposure to the causative agents. They identified 39 original studies documenting complete recovery from asthma (n = 1681 patients) and 28 with
improvement in nonspecific bronchial hyperresponsiveness (n = 695 patients). The
mean duration of follow-up was 31 (range 6–240) months in studies of symptomatic recovery and 37 (range 6–240) months amongst studies of nonspecific bronchial
hyperresponsiveness. However, there is not much information on quantification of
exposure prior to and after what is called cessation. Hence, data should be interpreted with caution.
According to this review, rates of symptomatic recovery varied broadly, with a
pooled estimate of 32% (95% CI 26–38%). These rates were lower with increasing
age and among clinic-based populations. Symptomatic outcomes worsened with
increasing age and – not significantly – with the duration of symptomatic exposure:
Patients with the shortest durations of exposure (b 76 months) had a slightly higher
rate of recovery, but still it was on average only 36% (95% CI 25–50%). The fact
102
Natural history and prognosis
that on average only one third of patients with OA will recover fully from their
disease, despite avoidance of the causative agent, seems not to be related to the
duration of avoidance (Fig. 1).
Figure 1.
Determinants of complete symptomatic recovery from occupational asthma after cessation
of exposure and a mean follow-up time of 31 (range 6–240) months. Data were collected
in a systematic review of the literature, based on 39 studies with 1681 patients. The mean
proportion of subjects with complete symptomatic recovery from asthma at follow-up was
32% (HMW, high-molecular-weight, LMW, low-molecular-weight). Reproduced from [9]
with permission from BMJ Publishing Group Ltd.
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Dennis Nowak
Persistent nonspecific bronchial hyperresponsiveness at follow-up was present
in 73% of patients (95% CI 66–79%). This figure was higher in patients whose
disease was due to high-molecular-weight agents (approximately 90%) as compared
to those with disease due to low-molecular-weight agents (approximately 65%)
(Fig. 2).
Figure 2.
Determinants of persistent nonspecific bronchial hyperresponsiveness in patients with occupational asthma after cessation of exposure and a mean follow-up time of 37 (range 6–240)
months. The mean proportion of subjects with persistent nonspecific bronchial hyperresponsiveness was 73%. (HMW, high-molecular-weight, LMW, low-molecular-weight.) Reproduced from [9] with permission from BMJ Publishing Group Ltd.
Descatha and coworkers performed a pooled analysis of factors associated with
severity of OA with a latency period at diagnosis [10]. Their study population consisted of 229 consecutive subjects with OA recruited by four occupational health
departments and divided into two groups according to the severity of disease at the
104
Natural history and prognosis
time of diagnosis. On multivariate analysis, only a longer duration of symptoms
before diagnosis was slightly but significantly associated with a higher asthma severity (OR 1.12, 95% CI 1.05–1.18).
In the specific setting of routine surveillance programs in high-risk populations,
OA due, for example, to isocyanates can be diagnosed earlier and is often associated
with better outcome compared to the absence of such a program [11].
In the majority of patients sensitized to occupational agents, nonspecific bronchial hyperresponsiveness persists even several years after the end of exposure. In
these patients it is of particular practical importance to know whether or not they
may nevertheless respond to their specific agent. They may! Lemière and coworkers
demonstrated that, despite treatment [12, 13], the absence of asthmatic symptoms
and normal nonspecific airway responsiveness, subjects with a history of OA to
high-molecular-weight agents, e.g., flour, guar gum and psyllium, and high levels of
specific IgE to these agents responded within a few minutes after specific bronchial
challenges. Thus, patients with OA due to high-molecular-weight agents should
persistently avoid specific exposure even when they have become asymptomatic
and nonspecific airway responsiveness has returned to the normal range. Probably,
persistent immunological sensitization is a unique factor in causing persistence of
disease in these subjects [14].
Outcome of patients with continuous exposure
Patients with OA generally deteriorate if they are left in the same workplace. This
was demonstrated, for example, in patients with cedar asthma after an average follow-up of 6.5 years; one third of these patients showed marked deterioration [15].
Anees and coworkers [16] investigated the course of spirometric changes in patients
with OA predominantly due to low-molecular-weight agents. In 90 subjects in
whom FEV1 measurements had been performed at least 1 year before removal from
exposure (median 2.9 years), the mean rate of decline in FEV1 was 101 ml/year.
One year after removal from exposure, FEV1 had improved by a mean of 12.3 ml.
The mean decline in FEV1 was 26.6 ml/year in 86 subjects in whom measurements
were made for at least 1 year following removal from exposure, similar to the rate
of decline in healthy adults. Remarkably, the decline in FEV1 was not significantly
worse in current smokers than in those who had never smoked, and was not affected
by the use of inhaled corticosteroids.
These data seem to contrast findings of Marabini et al. [17] who reported that
regular treatment with inhaled corticosteroids and long-acting bronchodilators
seemed to prevent respiratory deterioration over a 3-year period in workers with
mild-to-moderate persistent OA who were still exposed at work to the occupational
cause of their disease. However, this was a small-scale study with only ten subjects
available for follow-up, with ten others retiring or changing jobs. Thus, a selection
105
Dennis Nowak
process may have contributed to the somewhat surprisingly favorable outcome.
Additionally, as the authors state, some of the patients reported a reduction of
exposure to the offending agent. Therefore, conclusions from these data should be
drawn with great caution.
Inflammation and airway remodeling in the course of occupational asthma
Maghni and coworkers found that patients with OA who retain their bronchial
hyperresponsiveness for several years after removal from exposure to the causing
agent exhibit persistent airway inflammation with eosinophilia and neutrophilia in
induced sputum [18]. Thus, inflammation seemed to be self-sustained even in the
absence of exposure to the asthmagenic agent. Maestrelli commented on these data
that low-molecular-weight chemicals responsible for occupational sensitization once
inhaled may attach to proteins, although these compounds are unlikely to remain in
the body for years [19]. The same was considered even more valid when the sensitizing agent is a protein. Therefore, if the mechanism of airway inflammation in these
patients with persistent asthma is independent of exogenous stimulation, allergen
avoidance alone will not be sufficient to produce a favorable outcome.
Saetta and co-workers [20] studied airway wall remodeling in sensitized subjects
with OA caused by diisocyanates both at the time of diagnosis, and 6–21 months after
cessation of exposure to toluene diisocyanate. The cessation of exposure to the sensitizing agent was associated with a reduced, but still – compared to normal – pathologically increased thickness of the basement membrane and with a reduced number
of subepithelial fibroblasts, mast cells, and lymphocytes in the bronchial mucosa, suggesting a remodeling of the airway wall with the avoidance of the specific stimulus.
In a comparable setting, Piirilä and coworkers investigated inflammatory
changes in patients with diisocyanate-induced asthma after initiation of inhaled
steroid treatment at a mean period of 7 months (range 3–60 months) after cessation
of exposure [21]. The count of mast cells in bronchial mucosa decreased and that
of macrophages increased. During the first year, interleukin (IL)-4 level in mucosa
was significantly higher than in controls, but its level decreased during follow-up.
IL-6, IL-15, and tumor necrosis factor-A mRNA levels were significantly higher in
patients with bronchial hyperresponsiveness as compared to those without. Therefore, inflammation may persist in diisocyanate-induced asthma despite inhaled
steroid medication.
Fatal outcomes
Besides anaphylaxis to occupational sensitizers, OA may be a fatal condition:
Exposure to diisocyanates [22, 23], baking flour [24] and shark cartilage dust [25]
106
Natural history and prognosis
has been reported to cause death in sensitized workers. Whether or not the patient
reported by Chester et al. [26] was sensitized to diisocyanates or an irritative mechanism caused his fatality is not known. Stanbury and coworkers recently reported
an acute death of a young asthmatic waitress associated with work-related environmental tobacco smoke in a bar [27].
Outcome of reactive airways dysfunction syndrome
Malo and coworkers studied the long-term outcomes of acute irritant-induced
asthma [28]. In this cohort study of 35 subjects, the causal agent was chlorine in
the majority (n = 20). At reassessment after a mean interval of 14 ± 5 years, all subjects reported respiratory symptoms, and 24 (two thirds) were on inhaled steroids.
There were no significant improvements in FEV1 and FEV1/FVC values. Among 23
subjects with methacholine tests at follow-up, only 6 had normal levels of responsiveness. Greven et al. [29] investigated respiratory effects among 138 emergency
services first responders and residents with exposure to combustion products in the
aftermath of a chemical waste depot fire. Identified by telephone interview 6 years
later, subjects with persistent respiratory symptoms were suspected as having reactive airways dysfunction syndrome (RADS). Persistent respiratory symptoms and
bronchial responsiveness were associated with exposure to combustion products of
that fire. Thus, the long-term adverse outcome of RADS should generally be taken
more into consideration when managing incidents to limit exposure to airway irritants.
Conclusion
Available data on the prognosis of OA suggest that on average, only one third of
patients will lose their symptoms, and nonspecific bronchial hyperresponsiveness
may persist in the majority. Although data are insufficiently consistent to allow
individually tailored advice with a high positive predictive value, there is evidence
that continued exposure, once the disease has developed, leads to a worse prognosis,
and that early removal from exposure is associated with a better prognosis. Recently
published evidence-based guidelines for the prevention, identification, and management of OA [30] therefore summarize that:
-
-
symptoms and functional impairment of OA caused by various agents may persist for many years after avoidance of further exposure to the causative agent
(evidence 2+),
the likelihood of improvement or resolution of symptoms or of preventing deterioration is greater in workers who have
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Dennis Nowak
- no further exposure to the causative agent (evidence 2++),
- relatively normal lung function at the time of diagnosis (evidence 2+),
- shorter duration of symptoms prior to diagnosis (evidence 2+).
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Mechanisms of allergic occupational asthma
Xaver Baur
Ordinariat und Zentralinstitut für Arbeitsmedizin und Maritime Medizin, Universität Hamburg,
Hamburg, Germany
Abstract
High-molecular-weight agents are a major cause of allergic occupational asthma in the workplace.
High-molecular-weight agents comprise proteins from plant, microorganism or animal origin in
the 10–60 kDa range. A few occupational asthma allergens are man-made chemicals such as isocyanates or acid anhydrides. Allergens with a major public health relevance are derived from flour,
latex, enzymes and laboratory animals. The structures of antigenic determinants and mechanisms
of many occupational allergens have been elucidated, whereas those of others, e.g. of platinum,
recognized by immunocompetent cells are still obscure.
The underlying immune mechanisms of allergic occupational asthma correspond to type I
allergy, i.e., antigen recognition and processing by antigen-presenting cells, induction of the Th2
immune response resulting in the production of antigen-specific IgE antibodies, and finally release
and generation of bronchospastic and inflammatory mediators by mast and other cells.
The pathological mechanisms of allergic and non-allergic occupational asthma are relevant to
diagnostics, management, and prevention, and are also briefly covered in this chapter. Related to
this chapter is a useful listing of know occupational allergens, of high and low molecular weight,
included in an Appendix.
Introduction
Asthma characterized by variable airflow obstruction due to immunological mechanisms against agents occurring in the workplace is called ‘allergic occupational
asthma’ (allergic OA) (Fig. 1). Immunological mechanisms associated with allergenspecific IgE antibodies have been identified for most causative high-molecular weight
(HMW) and for some causative low-molecular weight (LMW) occupational agents.
The importance of other immunological mechanisms initiating airway inflammation
without detectable IgE antibodies needs further investigations (see below).
Typically, allergic OA has a latency period, which differs from ‘non-allergic
OA’ that is caused by exposure to irritant (non-allergenic) gases, fumes or particles
(Tab. 1). Non-allergic OA or irritant OA encompasses the reactive airways dysfunction syndrome (RADS), sometimes even occurring after a single exposure but also
after multiple exposure events to high concentrations of nonspecific irritants.
Occupational Asthma, edited by Torben Sigsgaard and Dick Heederik
© 2010 Birkhäuser / Springer Basel
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Xaver Baur
Work-related asthma (WRA)
Occupational asthma, OA
(New onset WRA)
Allergic
(IgEmediated)
OA
OA
due to
unknown
pathomechanisms
Work-aggravated
(exacerbated) asthma
Irritant
OA
Figure 1.
Schematic representation of occupational asthma (OA) as part of work-related asthma.
Table 1. Specific aspects of allergic occupational asthma (OA) and differences in comparison
with non-allergic (irritant) OA
Allergic OA
Non-allergic (irritant-induced) OA
Causes
Mainly HMW and some LMW agents
Airway irritants
Mechanisms
Specific IgE antibodies
Acute or chronic irritant injury to
bronchial mucosa
Essential features
Latency period of exposure and
sensitization prior to onset of
symptoms
Mostly sudden onset without latency
period; evidence for chronic low-dose
pathogenesis (rare)
Evidence of causal
relationship
Specific IgE antibodies, positive skin
prick test results
Temporal relationship between
exposure to irritant agents and
the (mostly rapid) onset of asthma
symptoms
Diagnostics
Assessment of obstructive
ventilation pattern, bronchial
hyperresponsiveness, and eosinophilic
inflammation associated with exposure
Assessment of obstructive
ventilation pattern, and bronchial
hyperresponsiveness associated with
exposure
Serial PEFR plus symptom diary
(Serial PEFR, if possible during relevant
exposure)
Specific inhalation challenge
(Specific inhalation challenge rarely of
diagnostic value)
Improvement or normalisation after
removal from exposure source; airway
hyperresponsiveness may persist
Improvement after removal from
exposure source; frequently persistent
airway hyperresponsiveness
Outcome
HMW, High-molecular weight; LMW, low-molecular-weight; PEFR, peak expiratory flow recordings
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Mechanisms of allergic occupational asthma
Pathophysiology and immunology of allergic OA
Initial pathophysiological mechanisms of allergic OA differ fundamentally from irritant OA (Tab. 1), although similar inflammatory changes have been described for
the chronic course of both disorders. Furthermore, there is no difference between
asthma caused by allergens from the general environment and asthma caused by
occupational allergens, as shown by various investigations including sputum cytology, bronchoalveolar lavage (BAL) analyses, bronchial biopsies and postmortem
lung tissue studies.
The most relevant involved mechanisms, cells and cytokines, are shown in Figure 2.
Inhaled occupational allergens gain access to the viable airway epithelium where
they engage and activate local dendritic cells, which keep mucosal surfaces under
surveillance. Allergens are processed by these cells, bind to major histocompatibility complex class II (MHC-II) molecules, and their fragments (highly polymorphic
Figure 2.
Scheme on immune mechanisms, mediators and pathophysiology of type I allergy.
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Xaver Baur
short peptides) are then transported by these cells to regional lymph nodes and
presented to T lymphocytes, which recognize them by their T cell receptors (TCR).
The cytokine milieu is critical to T cell differentiation in Th1 or Th2 responses.
IL-12 production leads to Th1 phenotypes, and increased IL-4/IL-13 production
leads to Th2 phenotypes. The Th2-dominant cytokine response drives the synthesis
and secretion of allergen-specific IgE antibodies by B cells (plasma cells). IgE regulates the expression of its own high-affinity IgE receptors (FcERI) and low-affinity
IgE receptor (CD23) on the surface of mast cells, basophils and possibly of macrophages, dendritic cells, eosinophils and platelets. IgE-dependent up-regulation of
FcERI and CD23 receptors subsequently amplifies immunological reactions. It leads
to a greater release of mast cell and basophil mediators at lower concentrations of a
specific allergen. Upon new exposure, the allergen cross-links between these specific
IgE antibodies on cell surfaces, gives rise to a cascade of events, and leads to an
inflammatory cell activation with subsequent synthesis and/or release of a variety
of preformed mediators (e.g., histamine) and newly formed inflammatory ones (e.g.,
prostaglandins, leukotrienes). These mediators orchestrate the inflammatory reaction in bronchial mucosa and submucosa (Fig. 2).
An interesting finding is the cleavage of the tight junction protein occludin by
allergenic proteases, e.g., from house dust mites or moulds, which damage the airway epithelium barrier and subsequently increase epithelial permeability and stimulation of the release of mediators. This also orchestrates local immune responses and
the inflammatory process [1, 2].
Airway remodeling, as typically found in bronchial asthma [3, 4], also takes
place in OA. It can be interpreted as an exaggerated and uncontrolled injury repair
process influenced by type and intensity of airway injury and modulated by host
as well as genetic factors. It involves epithelial changes, increases in smooth muscle
mass and subepithelial collagen deposition, proteoglycans and elastin content,
angiogenesis, cartilage changes, goblet cell and glandular hyperplasia. Airway modeling may lead to persistently increased airway responsiveness and mucous production, airflow limitation, and probably to a decline in lung function [5]. Besides its
detrimental effect it may protect against excessive bronchoconstriction and inflammation.
Typical morphological findings in airways of allergic OA patients include:
- epithelial desquamation or hyperplasia;
- an increased number of inflammatory cells, especially of eosinophils, in mucosal
and submucosal layers (demonstrated by bronchial biopsies); they are also found
in sputum and BAL;
- evidence for the activation of eosinophils and lymphocytes;
- increased airway wall thickening;
- increased thickness of the basement membrane, especially of the reticular layer
due to interstitial cross-linked collagens produced by myofibroblasts;
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Mechanisms of allergic occupational asthma
-
-
airway smooth muscle hyperplasia, hypertrophia, an increased secretion of
cytokines as well as growth factors recruiting inflammatory cells and stimulating
the production of extracellular matrix proteins; submucosal and peribronchial
vessels are dilated, congested and exhibit thickening of arterial media [4];
increased NO concentrations in exhaled air (FeNO) after exposure to causative
allergens, isocyanates, ozone, swine confinements [6].
It should be noted, however, that there is no consistency with regard to the parallel
changes in inflammatory cell counts and/or their activation status on the one hand
and asthma severity on the other hand.
Exposure cessation does not always lead to an improvement of abnormal morphological and cellular changes and clinical findings [7]. Subepithelial collagen
thickening may reverse after exposure termination and treatment with inhaled
steroids.
Determinants of allergic OA
Atopy affecting approximately one third of the population, and defined as the tendency to produce specific IgE antibodies to environmental allergens like those from
house dust mites, pollen, and cat or dog fur, modifies the risk of allergic OA resulting
from HMW sensitizers as found in bakers (especially in those with hay fever) [8–12],
laboratory animal workers (in those sensitized to pets) [13–16], subjects exposed to
detergent enzymes, certain reactive dyes, latex [17], and other HMW allergens [18].
In contrast, atopy does not modify the risk for developing asthma caused by isocyanates, acid anhydrides, platinum salts or plicatic acid of red cedar wood. An increasing number of studies show convincing evidence for exposure-response relationships
in allergic OA, with higher exposure levels associated with specific sensitization,
symptoms, and obstructive ventilation patterns [19–30]. The exposure-response
relationships show mostly a linear shape, but bell-shaped relations have also been
described for some OA allergens [12]. There is a need for prospective studies with
more detailed investigations on dose and timing of occupational exposures.
Recently there has been increased interest in the role of specific genes and geneenvironment interactions, which are often complex and non-linear. Generally, most
studies on allergic asthma are small and replication studies have seldom been published. Mostly candidate gene studies have been performed focusing on polymorphisms in genes responsible for metabolism of chemicals (like for isocyanates) or
genes coding for certain steps in immunological pathways such as antigen presentation [human leukocyte antigen (HLA) genes]. Very few gene environment studies
have been conducted. One of the more interesting ones refers to a promoter single
nucleotide polymorphism in the CD14 gene (–159 T to C). This polymorphism and
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Xaver Baur
exposure to endotoxin were found to be associated with a decreased frequency of
allergic asthma in children living on farms [31–33]. One early study showed that
A-1-antitrypsin alleles were associated increased hyperresponsiveness in farming
students only, indicating a gene-environment interaction [34]. Recent studies provide strong evidence for a genetic basis of increased skin and mucosa permeability
in atopics. This involves defects of filaggrin, facilitating terminal differentiation of
the epidermis and formation of a skin barrier [35, 36]. Its mutations are linked with
eczema-associated asthma and asthma severity [37]. Furthermore, overexpression of
Th2 cytokines down-regulates filaggrin expression [38].
Other polymorphisms that code for genes of HLA class II or transmembrane
proteins or respiratory anti-oxidant mechanisms may also explain susceptibility to a
number of causative occupational agents; however, respective definitive risk factors
cannot be provided yet [39–44]. Genetic studies and gene-environment studies are, at
the moment, mainly of mechanistic interest. Applications for risk profiling, diagnosis
or personalized treatment or prevention over the short term are not expected.
Cigarette smoking increases the risk of specific sensitization and OA due to several LMW agents [45–49]. This was shown in workers of platinum refineries [50,
51], snow-crab processing plants [52], and subjects exposed to tetrachlorophthalic
anhydride [53] or Ispaghula dust [54].
Allergic occupational rhinitis frequently occurs as a co-morbid condition in
allergic OA. Typically, allergic occupational rhinitis or rhinoconjunctivitis develop
before the onset of allergic OA, indicating an increased OA risk in affected subjects
[22, 26, 55–60].
Occupational allergens
List of known occupational allergens
There are about 350 OA-inducing allergens, mainly HMW compounds representing airborne (glyco)proteins from plants, microorganisms, and animals (see Tab. 2),
and eliciting IgE-mediated hypersensitivity. Several LMW agents may also elicit IgE
responses; some of them thus seem to be complete allergens. Other LMW agents
such as acid anhydrides and isocyanates form allergenic conjugates upon reaction
with autologous human proteins. Specific IgE antibody responses may be directed
against the newly formed structures (especially against the binding regions of such
conjugates behaving as new antigenic determinants) or against the haptenic ligand
(the latter was shown for phthalic acid anhydride and himic anhydride). There is
evidence that ring structures, positions of double bonds and methyl group substitutions are critical determinants of IgE-mediated sensitization [61, 62]. Many of the
allergenic LMW agents also behave as irritants, i.e., OA may be due to the IgEmediated pathway or, especially at high concentrations, due to irritative effects. This
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Mechanisms of allergic occupational asthma
Table 2. Allergenic agents reported to cause OA: Groups and important examples
(Complete list available at: http://www.uke.uni-hamburg.de/institute/arbeitsmedizin/
mPublikationen “Allergenic agents reported to cause occupational asthma”) (accessed 6
November 2009)
Group
Important examples
Microorganisms and their products
Aspergillus enzymes, e.g., fungal A-amylase,
detergent enzymes
Plants
Flour, grain
Latex
Wood dust
Flowers
Animals
Rats, mice
Cows
Birds
Storage mites
Insects
Seafood
Chemicals
Isocyanates
Acid anhydrides
Metal dust, e.g., platinum salts
Synthetic drugs
Hairdressing chemicals
means that the detection of respective IgE antibodies is a specific but not necessarily
a sensitive diagnostic marker of OA caused by such LMW agents.
For some occupational agents such as plicatic acid and morphine, respective IgE
antibodies seem not correlated with clinical findings. This unexpected finding raises
the question of the specificity of IgE tests used or the absence of IgE.
For details on OA-inducing occupations and confinements comprising some
specific, heterogeneous or unidentified allergens, see the Appendix.
Clinical aspects
Exposure of a sensitized and hyperresponsive subject to a causative allergen elicits
an early asthmatic reaction, which is characterized by smooth muscle contraction,
mucosal edema and an inflammatory response. A late asthmatic reaction may take
place several hours afterwards, which is associated with a prolific influx of inflammatory cells and followed by remarkable and long-term inflammatory reactions and
an increase in bronchial hyperresponsiveness.
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Diagnosis of allergic occupational asthma
The initial suspicion of OA is mostly expressed by the general practitioner, pneumologist, allergologist or occupational or factory physician due to work-related
asthma symptoms. Diagnostic measures should be performed before the worker
leaves her/his workplace since prolonged avoidance of contact with the causative
substance(s) can reduce susceptibility and lead to false-negative diagnostic results.
A basic clinical examination and environmental evaluation should be performed
in any suspicious case. If there is evidence for an occupational cause of asthmatic
symptoms and/or disorders a more detailed assessment should follow to establish
a working hypothesis of the disorder. Evaluation tests will confirm or definitely
negate the provisional diagnosis. These measures usually require considerable
effort and expertise. For details, see Figure 3 and 4. One should realize that specific
mechanisms involved in the different phenotypes of OA related to different causes
determine to some extent the sequence and choice for specific diagnostic procedures.
This makes the diagnosis a complicated process and the likelihood of making wrong
Figure 3.
Stepwise scheme for the diagnostic procedure to confirm or exclude OA. * Consider possibility of false-negative testing of nonspecific bronchial hyperresponsiveness. In case of positive
allergological test results, the diagnosis is allergic OA.
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Mechanisms of allergic occupational asthma
Figure 4.
Specific inhalation challenge test by the isocyanate MDI eliciting a dual asthmatic response.
The 51-year-old foam worker has suffered from work-related asthma attacks for 15 months
as well as from nocturnal asthmatic symptoms that could not clearly be related to a causative
agent so far.
decisions is always present. In brief, the diagnostic workup consists of the following
steps with some relevant details for each step related to mechanisms:
-
-
-
The detailed occupational history and the detailed medical history (Tab. 1 and
3) are the central parts of the diagnostic algorithm;
Allergic OA has to be differentiated from irritant OA (see basic toxicological
information for an agent, check medical literature, interpret results of allergological tests);
Commercially available well-standardized allergen extracts should be used for
allergological testing and specific inhalative challenge tests; mostly they have to be
supplemented by self-made extracts of HMW agents occurring in the workplace;
The use of standardized and sensitive methods for the measurement of specific
IgE antibodies in serum is highly recommended if the routine skin prick testing
is not possible or its results are not reliable;
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Table 3. Components of the medical, occupational, and environmental history
Components of the medical, occupational, and environmental history
A. History of the present illness
1. Detailed record of the circumstances resulting in the onset and worsening of disease
2. Temporal relationships between recurrent exposures and disease exacerbations
3. Course and rate of airway diseases in the particular workplace/branch
4. Asthma severity at the time of initial evaluation
B. Medical history
1. Premorbid medical history, e.g., childhood asthma, hay fever, pet allergy
2. Associated symptoms and concomitant diseases
C. Occupational and environmental history
1. Type (quality) of noxious substances in the workplace (e.g., allergens, irritants,
carcinogens, etc.)
2. Intensity (concentrations) of exposure by inhalation, and skin contact
3. Cumulative dose during working life
4. Use of protective equipment
-
-
The course of lung function parameters and symptoms before, during and after
occupational exposure has to be evaluated in detail. Further, exact analyses of all
medical reports before, during and after employment including medical surveillance data should be performed; Table 4 gives an overview on indications and
further details of specific inhalative challenge tests.
If the occupational exposure generated a new onset of asthma or a significant
aggravation of preexisting asthma, the disorder and its deteriorating proportion
have to be reported to the responsible insurance institution for occupational
diseases, be recognized and compensated as an occupational disease (respective
national legal definitions and regulations have to be observed).
New diagnostic tools
New additional diagnostic tools include measurements of the fraction of exhaled
nitrous oxide (FeNO), and analyses of induced sputum and exhaled breath condensate during occupational exposure. These methods have been shown to provide
valuable information on occupationally induced allergic airway diseases and differential diagnoses [63, 64].
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Mechanisms of allergic occupational asthma
Table 4. Overview of specific inhalative challenge tests: indications, methodology, advantages and limitations
Indications
- uncertain diagnosis and unclear etiology
- the respective information is necessary for preventive and/or
therapeutic measures or compensation.
Methodology
- generate constant, well-defined non-irritative air concentrations
- start with a concentration that is expected not to cause a response
and increase it in several ~15-min intervals, each with an ~3-fold
increase in concentration up to the workplace atmosphere level or
OEL (TLV)
- monitor air concentration continuously with validated equipment,
e.g., isocyanates by an MDA 7700 device.
Advantages
- Identification/exclusion of an individual occupational agent as OA
cause.
Limitations
- High concentrations of an irritative agent may lead to unspecific
effects, i.e., to a false-positive result
- A false-negative result may occur due to:
s anti-asthmatic treatment
s a long latency period
s use of an inappropriate substance or too low concentration of the
causative agent
s cumulative effects of an occupational agent over days or of several
agents with additive effects present in the workplace (the latter two
cannot be reproduced in the laboratory).
OEL, occupational exposure limit; TLV, threshold limit value
Appendix: Occupational asthma-inducing occupations and work environments comprising some specific, heterogeneous or unidentified allergens
Animal confinements and farm working
The prevalence of rat allergy among laboratory animal workers ranges from 12%
to 31% [65]. Cross-sectional and cohort studies revealed that the exposure levels
to rat urinary aeroallergens correlated positively with the frequency of positive
skin test results as well as with work-related upper and lower airway responses [8,
66–68]. Atopic workers had a more than threefold increased sensitization risk at
low allergen levels than non-atopics. Major allergens in rat excreta and epithelium
involve A2M-globulin (17 kDa), prealbumin (21 kDa) and a 23-kDa protein. Similar
results were reported for mouse allergens/urinary proteins [65, 69]. An increase in
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asthma prevalence also occurs in farm animal confinements [70–73]. Cow allergens
were reported to be a major cause of respiratory allergies of farmers [74–76]. Concentrations as low as 1–20 Mg (atopics), and 25–50 Mg (non-atopics) of the major
cow allergen Bos d 2 per gram dust were found to be significantly associated with
specific IgE antibodies [77]. Furthermore, Rautiainen et al. [78] reported that the
level of antibodies to bovine epithelial allergens among exposed subjects reflects the
level of clinical allergies.
Working in swine confinements [79–83], poultry confinements [84, 85], poultry
slaughter houses [86, 87] or contact with raw poultry [88] causes lung function
declines and OA. Further, a dose-response relationship between daily working hours
inside animal houses and symptoms was established for pig farmers [82]. However,
recent publications indicate that endotoxins represent the predominant cause of
obstructive airway diseases in poultry and swine confinement workers [81, 89]. Irritating gases such as ammonia and NOx may also elicit OA in these environments.
Thus, animal and farm working is associated with an increased prevalence of OA
and also of chronic obstructive pulmonary disease [82]. In addition to specific animal allergens, causative exposures in animal confinements comprise hay and grain
dusts and other animal feed as well as storage mites [90]. Allergic reactions and
irritant OA have to be differentiated in these workers [91].
For flour mill workers, Peretz et al. [12] also described a positive association
between exposure to up to ~10 Mg EQ/m3 and sensitization, but a decline in sensitization at higher concentrations The healthy worker effect may have contributed to
these findings [92, 93]. Recently, Cullinan et al. [23] reported an annual incidence
of work-related chest symptoms of 4.1%, and their association with a positive skin
prick test to flour or A-amylase of 1% (sensitization to A-amylase was a little more
frequent than that to flour). Interestingly, predominantly atopics became symptomatic and sensitized to A-amylase; and exclusively atopics were sensitized to flour.
Industrial enzyme production
A variety of natural and an increasing number of genetically modified recombinant
enzymes produced on a large-scale behave as potent inhalative allergens [94]. These
include many mould enzymes, detergent enzymes derived from Bacillus subtilis and
other bacteria as well as plant proteins such as bromelain (a pineapple protease) or
papain (derived from the papaya fruit). The latter enzyme is used as meat tenderizer
and capable of sensitizing workers in industrial kitchens. Obviously all enzymes
have to be regarded as inhalative allergens affecting mainly pharmaceutical factory
and laboratory workers [95].
Fungal A-amylase, derived from Aspergillus oryzae is widely used as a baking
additive; sensitizing air concentrations in bakeries are in the ng/m3 range. In the late
1960s, the introduction of alkaline heat-stable enzymes (proteases, amylases, cel-
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Mechanisms of allergic occupational asthma
lulases) in the detergent industry was associated with estimated enzyme air concentrations in the workplace of ~300 ng/m3 and higher; 40–50% of the workers were
sensitized and developed asthma and/or rhinitis. Follow-up studies showed high
exposures (estimates were based on the dustiness of workplace atmospheres) and
atopy to be related with an increased sensitization incidence. The highest sensitization occurred within the first 2 years of observation, although follow-up was short
[96]. Nevertheless, Cullinan et al. [24] found 19% of detergent workers exposed to
enzymes (the geometric mean concentration was 4.25 ng/m3) to be sensitized; 16%
had work-related respiratory symptoms. In 2007, ACGIH [97] published a threshold limit value (TLV)-short-term exposure limit (STEL)-C (ceiling) of 0.06 Mg/m3 for
the bacterial protease subtilisin.
More recently, it has been established that aeroallergens containing proteases
may have a critical role in overcoming airway tolerogenic mechanisms that ordinarily exclude allergic responses to inhaled allergens. Proteases, e.g., from mites
and moulds, probably do not only behave as typical allergens. They permit allergic
responses by enhancing antigen presentation via the degradation of tight junction
structures. Moreover, protease activation of epithelial cell protease-activated receptors (PARs) may facilitate allergic responses to aeroallergens by directly inducing
the expression of chemokines required for maximal leukocytic activation and infiltration. The latter may induce a non-allergic, innate inflammatory response via the
release of pro-inflammatory cytokines.
Floricultures, florists; greenhouses
Floriculture and greenhouse workers have an increased risk of sensitization and OA
[82, 98–101]. Many fresh or dry flowers and non-flowering green plants were found
to cause OA, frequently also rhinitis, and/or dermatitis including: amaryllis (Amaryllis hippeastrum) [102], asparagus (Asparagus officinalis) [103], aster (Asteraceae)
[98, 104, 105], baby’s breath (Gypsophila paniculata) [106–108], bells of Ireland
(pollen, Molucella laevis) [109], canari palm pollen (Phoenix canariensis) [110], carnation (Dianthus caryophillus) [111–113], Carthamus tinctorius and yarrow (Achillea millefolium) [114], Christmas cactus (Schlumbergia) [115], Chrysanthemum
leucanthemum, Chrysanthemum spp. and other flowers [105, 116–118], compositae
such as chamomile (Matricaria chamomilla) [104], Easter lily (Lilium longiflorum)
[119, 120], eggplant (Solanum melongena) [121], freesia (Freesia hybrida) [117, 122,
123], G. paniculata [108], German statice (Limonium tataricum) [124], hyacinth
(Hyacinthus orientalis) [125], Liliaceae [102], Madagascar jasmine (Stephanotis
floribunda) [126], mimosa pollen (Acacia floribunda) [104, 127], narcissus (Narcissus pseudonarcissus) [128], paprika (Fructus capsici) [122], pea, sweetpea (Lathyrus
odoratus) [129], peach (Prunus persica) [130], poppy (Papaver somniferum) [131],
rose (Rosa sp.) [132, 133], safflower (Carthamus tinctorius) [114], saffron pol-
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len (Crocus sativus) [134], spathe flowers (Spathiphyllum wallisii) [135], statice
(Limonium tataricum) [124], sunflower (Helianthus annus) [136–138], Tetranychus
urticae [139], tulip (Tulipa) [117, 140, 141], umbrella tree (Schefflera) [142], various
decorative flowers [98, 104, 117], weeping fig (Ficus benjamina) [142–144].
The predatory mites Amblyseius cucumeris [145], Phytoseiulus persimilis and
Hypoaspis [146, 147] were also reported to cause OA among horticulturists working in greenhouses.
Further causative allergen sources are the red spider mite (Tetranychus urticae)
[139, 148] and biopesticides containing Bacillus thuringiensis or Verticillium lecanii
[149]. Furthermore, high indoor temperatures und humidity in greenhouse facilities may result in intensive mould growth, particularly of Cladosporium herbarum,
penicillium, aspergillus and alternaria spp., which have been shown to be associated
with an increased asthma prevalence [150]. For more details, see chapter “Exposure
to moulds”.
Exposure to other important plant allergens
A variety of plant components and plant products represent important occupational respiratory allergens, e.g., baking flour, grain and soy bean dust, natural
latex. They also comprise aniseed powder [151], asparagus [103], banha [152],
carrot [153], chicory [154], fenugreek [155], garlic dust [156, 157], ginseng [158],
aromatic herbs [159], hobs [160], ipecacuanha [161], kapok [162], licorice roots
[163], lycopodium powder [164], ‘Maiko’ (derived from the tuberous root of devil’s
tongue) [165], mushroom powder [166, 167], onion [168], peach leaves [130],
pectin powder [169], potato [170], freeze-dried raspberry [171], rose hips [133],
sanyak [172], sarsaparilla root [173], various spices such as coriander, mace [174],
fermented tea [175–177], green tea [178, 179], herbal teas (sage, chamomile, dog,
rose, mint and others). Vegetable gums derived from plant materials and containing carbohydrates produce mucilage upon reaction with water. They are frequently
used in the industry and in pharmacies. Exposed workers may develop respiratory
allergies inducing OA. Mostly printers exposed to acacia gum [180–183], hairdressers having contact to karaya [184], pharmaceutical workers and nurses handling
psyllium seeds [185–196] and carpet manufacturers in contact with guar gum [197]
are affected.
Hairdressing salons
OA-inducing hairdressing chemicals comprise persulfate salts, p-phenylenediamine,
reactive dyes, henna, other dyes and natural latex and hairdressers are thus exposed
to a complex mixture of HMW and LMW sensitizers and irritants [198–206].
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Mechanisms of allergic occupational asthma
Drug-manufacturing plants
Drug manufacturing and application may be associated with the generation of airborne dust containing particles of raw materials, intermediate or end products capable of causing OA. These materials and products include amoxicillin, amprolium
(the latter also causes asthma in poultry feed mixers), ceftazidine, cephalosporins,
cimetidine, hydralazine, ipecacuanha, isonicotinic acid hydrazide, methyl dopa,
mitoxantrone, opiate compounds, penicillamine, penicillin and ampicillin, phenylglycine acid chloride, piperacillin, psyllium, salbutamol intermediate, spiramycin,
tetracycline and tylosin tartrate. An IgE-mediated mechanism has not been proven
for all of these compounds.
Isocyanate application
Isocyanates are increasingly used for the production of polyurethane foam, elastomers, adhesives, varnishes, coatings, insecticides and many other products. These
highly reactive chemicals have become the number 1 of occupational airway sensitizers in several western countries. The study by Petsonk et al. [207] should be mentioned, which evaluated respiratory health in a new wood products-manufacturing
plant using diphenylmethane-4,4’-diisocyanate (MDI) and its prepolymer. In the
follow-up survey 15 out of 56 workers (27%) in areas with the highest potential
exposures to liquid isocyanates had an onset of asthma-like symptoms. In addition,
47% of workers with MDI skin staining and 19% without skin staining developed
such symptoms, which were associated with variable airflow limitation and specific
IgE to MDI-HSA, while controls did not develop any OA cases. Our cross-sectional
studies performed in two factories showed in comparison to the group exposed
to 5–10 ppb MDI significantly fewer symptomatic subjects, lung function impairments and specific IgE antibodies in the group exposed to less than 5 ppb toluene
diisocyanate (TDI) [208]. Tarlo et al. [209] found evidence for higher isocyanate
exposures in facilities with OA claims. In another study [210], specific sensitization
did not occur at TDI concentrations b 0.02 ppm over 3 years, whereas elevated antibody levels were found in subjects who experienced accidental exposures without
a clear exposure-response relationship. There is evidence that dermal exposure to
isocyanates can induce OA [211, 212]. Only a minority of symptomatic isocyanate
workers show IgE antibodies to diisocyanate-HSA conjugates [213–218]. Several authors observed isocyanate exposure-dependent lung function declines in the
occupational exposure limit (OEL) range [219–223]. It is worth mentioning that in
most western countries OELs for monomer diisocyanate exposure have been set at
10 ppb. From the clinical point of view, this value seems to be too high. According
to literature, 5–2.5 ppb considering all isocyanates in a particular workplace would
be health-based levels [224, 225]. OELs for isocyanates should consider gaseous as
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well as aerosol forms and also the increasingly used polyisocyanates or oligomers
causing similar disorders as monomeric diisocyanates. Moreover, the prevention of
isocyanate skin contact is obviously also an effective measure to reduce the risk of
respiratory disorders. The TLV-time weighted averages (TWAs) currently proposed
by ACGIH (2007) [97] are for TDI 0.005 ppm (TLV-STEL 0.02 ppm), for MDI
0.005 ppm and for HDI 0.005 ppm based on monomer exposure.
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140
Mechanisms of occupational asthma caused by
low-molecular-weight chemicals
Vanessa De Vooght, Valérie Hox, Benoit Nemery and Jeroen A. J. Vanoirbeek
K. U. Leuven, Faculty of Medicine, School of Public Health, Occupational, Environmental
and Insurance Medicine, Research Unit for Lung Toxicology, Leuven, Belgium
Abstract
Understanding the pathogenesis and working mechanisms of occupational asthma (OA) is crucial towards optimizing prevention and management of the disease. The study of the sensitizing
and asthma-inducing properties of low-molecular-weight (LMW) agents is evolving quickly. So
far, experimental research has shown that OA caused by sensitization to LMW agents does not
completely fit the pathways of the traditional allergic model, in which there is a central role for
immunoglobulin E. Furthermore, recent evidence indicates that chemical respiratory allergens may
induce respiratory tract sensitization by routes other than inhalation, such as dermal exposure.
Knowledge on OA induced by LMW is increasing, but the pathogenesis remains largely vague.
Dendritic cells, T cells, eosinophils, and several cytokines and chemokines are likely involved as
in atopic asthma. However, through subtle differences in T cell subpopulations, cytokine balances
and effector cells involved chemical-induced OA may well depend on processes that might differ
substantially from those of atopic asthma. Furthermore, the involvement of the transient receptor potential channels in chemical-induced OA and irritant-induced asthma is intriguing. Further
research in both humans and animals remains necessary to clarify the process of sensitization by
LMW allergens and the mode of action inducing the OA phenotype.
Introduction
The lungs are the primary target for a diverse spectrum or work-related dusts,
gases, fumes and vapors. Depending on the amount inhaled and on their physicalchemical properties, these agents have the capacity to cause annoyance, irritation,
corrosive changes and/or sensitization in the respiratory tract. Occupational asthma
(OA) is a type of asthma due to causes and conditions attributable to a particular
work environment, rather than stimuli encountered outside the workplace [1]. It
is characterized by a reversible airway obstruction of the airways associated with
bronchial hyperresponsiveness upon inhalation of workplace-related agents [2]. OA
has been implicated (directly or indirectly) in 9–15% of the cases of adult asthma,
making OA one of the most common presentations of occupational lung diseases
Occupational Asthma, edited by Torben Sigsgaard and Dick Heederik
© 2010 Birkhäuser / Springer Basel
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in many industrialized countries [3]. More than 350 agents have been reported to
cause OA [4].
Traditionally, OA is divided into two types. The first type is immunologically
mediated (or allergic) OA, in which sensitization against a workplace agent occurs
after a “latency period”. Immunologically mediated OA can be further divided into
the well-known classical IgE-mediated form, and the more elusive “poly-immunological” cellular form (non-IgE-mediated). The second type, non-allergic OA or
“irritant-induced” OA, is caused by exposure to irritant chemicals to which the
host does not become sensitized. In its most typical presentation, irritant-induced
asthma (IIA) is characterized by the absence of a latency period, because it is initiated by a sudden, acute exposure to high concentrations of an irritant. This form
of IIA is often called reactive airways dysfunction syndrome (RADS). Other forms
of IIA, caused by repeated exposures to irritants, are more controversial. Besides
these forms of OA, some exposures at work may also lead to pharmacological
bronchoconstriction and reflex bronchospasms [1, 5], but these reactions will not
be discussed further.
The prevalence of OA depends mainly on the causative agent and the intensity
of exposure [6, 7], and to some extent also on the distribution of individualdependent factors, such as atopy and smoking status [8]. The highest prevalence
of immunologically mediated OA has been reported in the detergent industry
(up to 50%), in which workers are exposed to proteolytic enzymes. In cohorts
of laboratory animal workers, prevalences of 30% of OA have been described.
However, the prevalence of OA is generally much lower. In most occupational
cohorts, prevalence varies between 9 and 15% [1]. Non-immunological OA is
generally considered to occur less frequently than immunologically mediated
asthma. The proportion of IIA among patients referred to an occupational lung
disease clinic has been reported to be 2–3% [9, 10]. When criteria were expanded
to one or more exposures to high levels of irritant, the prevalence of IIA doubled
to 6%, accounting for 17% of all OA patients participating in a study of Tarlo and
Broder [10]. One of the largest epidemiological studies published on IIA, concerns
workers of the New York City Fire Department who were exposed to a variety of
airway irritants during the rescue mission after the collapse of the World Trade
Center on 11 September 2001: 16% of a sample of these workers met the criteria
for IIA [11].
Depending on their molecular mass, agents causing OA can be divided into two
categories: (a) biological agents of high molecular mass (HMW) (>5 kDa), such as
proteins, glycoproteins and polysaccharides, and (b) chemicals of low molecular
mass (LMW) (<5 kDa), such as synthetic chemicals, natural compounds, drugs and
metals. HMW compounds generally induce OA via IgE-dependent mechanisms
comparable with asthma induced by pollen or house dust mite allergens [12, 13],
whereas many (although not all) LMW compounds appear to induce OA via pathways that do not involve IgE-dependent mechanisms.
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Pathophysiology
Immunologically mediated OA
LMW chemicals comprise an important subset of etiological agents of OA, including approximately 100 chemical entities [4]. Isocyanates, acid anhydrides, plicatic
acid from western red cedar, colophony fume, metals, complex platinum salts, persulfate salts, and some acrylates are just a few examples of important chemicals
causing OA.
Since LMW agents are non-immunogenic in their native state, it is assumed that
they must form a stable association with proteins to initiate an immune response.
These protein-hapten conjugates can be recognized and internalized by professional
antigen-presenting cells (APC) such as dendritic (DC) or Langerhans cells. Like
most HMW agents, these conjugates are presented to T cells, which initiate an
immune response and, possibly, asthma via an IgE-mediated mechanism or another
mechanism. Complex platinum salts and trimellitic anhydride (TMA) are LMW
asthmagens that are generally considered to induce asthma via specific IgE antibodies. These agents most likely possess a unique inherent ability to react directly
(or indirectly, after metabolic activation) with functional groups present on human
proteins [14, 15]. Not only albumin, but also other proteins such as keratine and
tubuline can serve as carriers to render LMW agents immunogenic [15, 16].
Wisnewski et al. [17, 18] showed that LMW asthmagens can conjugate with
proteins present on the surface of epithelial cells, thereby permitting presentation of
LMW asthmagens to the immune system in a hapten-like manner. This may facilitate the uptake of the protein-hapten conjugates by professional APC to initiate the
T cell response. If this is true for these LMW agents, then overall, the mechanism
by which LMW antigens are presented to T cells and the following cascade of B cell
activation plus IgE class switching, cross-linking of antigen and IgE on mast cells
and attraction of inflammatory cells would be relatively similar between LMW and
HMW compounds. Nevertheless, there are some questions and differences. For
example, it is not exactly known in which form LMW asthmagens are displayed
to responsive T cells. The way an antigen or hapten is processed, is dependent on
where the hapten-protein conjugate is produced. Endogenous antigens are processed
inside the cell, while exogenous antigens are processed through the endosomal pathway in DC. The binding of an LMW asthmagen (or its metabolite) to some lung
intracellular protein may give rise to an endogenous antigenic determinant, and this
may, therefore, be presented to CD8+ T cells by major histocompatibility complex
(MHC) class I [19]. However, the hapten may escape endogenous processing by cells
in the lung and enter the peripheral circulation to bind proteins in the circulation.
Such a chemical-modified antigenic protein is then processed by professional APC,
e.g., B cells, macrophages and DC, and presented to CD4+ T cells on MHC class
II [20].
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Depending on the pathway of LMW antigen presentation (MHC class I or
MHC class II), different types of immune responses might develop (CD4+ or
CD8+), which are categorized by their dominant cytokine secretion profile into T
helper (Th) type 1 (IL-2, IL-12, IFN-G), Th2 (IL-4, IL-13, IL-5), T regulatory (Treg)
(TGF-B, IL-10) and Th17 (IL-17). While previously it was suggested that Th1 and
Th2 cytokines counterbalanced each other, it has become clear that both Th1 and
Th2 cytokines are involved in OA caused by LMW antigens [21–23]. Th17 cells,
producing IL-17 – a potent attractant of neutrophils – are the latest T cells suggested to play a role in the proinflammatory pathway of OA [24]. While Th1, Th2
and Th17 cells are involved in proinflammatory pathways, Treg cells are thought
to dampen the immune (asthmatic) response, possibly explaining why the majority
of individuals do not develop adverse reactions to LMW asthmagen exposure [23,
25].
Besides LMW agents that initiate an IgE-mediated asthmatic response, there are
also LMW agents, such as diisocyanates and plicatic acid that do not act via specific
IgE antibodies, even though they lead to the same phenotypical characteristics as
IgE-mediated OA [26–29]. In humans, the airway inflammation process is indeed
similar in both IgE- and non-IgE-dependent asthma [13, 30, 31], and is characterized by the presence of eosinophils, lymphocytes, neutrophils, mast cells, and typical
features of airway remodeling [6, 31, 32]. Airway inflammation is accompanied by
a wide range of proinflammatory mediators and proteins. An influx of inflammatory cells, along with proinflammatory mediators can lead to a broad variety of
adverse effects, such as toxic damage, increased oxidative stress, and loss of barrier
integrity, contributing to long-term airway remodeling. Although in OA to LMW
asthmagens, CD4+ cells are associated with eosinophilia and airway inflammation
[32, 33], a role has been suggested for CD8+ cells in non-IgE-dependent OA [4, 23].
Interestingly, a small but significant proportion of T lymphocytes from the peripheral blood of subjects with OA induced by red cedar produce IL-5 and IFN-G after
stimulation with the conjugate of plicatic acid and human serum albumin, which is
indicative of a mixed Th1/Th2 response [34].
The fate of inhaled diisocyanates in the human body and the nature of the
antigen that is eventually produced are largely unknown, as is the case for most
chemicals that can induce OA [4]. Extracellular glutathione was able to prevent isocyanate induced toxicity in human epithelial cells [18]. Human monocytes exposed
in vitro to toluene diisocyanate (TDI)-albumin conjugates, undergo activation and
up-regulation of lysosomal genes, along with increased production of monocyte
chemoattractant protein-1 (MCP-1), and chitinase-1 [35]. Repetitive antigenic stimulation of in vitro cultured PBMCs obtained from subjects with diisocyanate asthma
revealed that these cells synthesized TNF-A, a non–IgE-dependent proinflammatory
cytokine, and MCP-1, but not IL-4 or IL-5 [35]. These observations are consistent
with the hypothesis that isocyanate-induced up-regulation of immune pattern-recognition receptors by monocytes and release of damage-associated molecular pat-
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terns from injured epithelium may be a mechanism by which isocyanates stimulate
the human innate immune responses and consequently influence the hypersensitivity
reactions [36].
Irritant-induced OA
Besides the allergic type of OA, there is another type of OA that is caused by exposure to airway irritants and may occur without a latency period in its most typical
presentation [9]. Originally, this disease entity was termed ‘reactive airway dysfunction syndrome’ (RADS). A case of RADS was defined as: (1) a documented absence
of preceding respiratory complaints; (2) onset of symptoms after a single exposure
incident or accident; (3) exposure to a gas, smoke, fume, or vapor with irritant
properties present in very high concentrations; (4) onset of symptoms within 24 h
after the exposure with persistence of symptoms for at least 3 months; (5) symptoms simulate asthma with cough, wheeze, and dyspnea; (6) presence of airflow
obstruction on pulmonary function tests and/or presence of nonspecific bronchial
hyperresponsiveness; and (7) other pulmonary diseases ruled out. In 1989 these
diagnostic criteria were modified by Tarlo and Broder, in the sense that patients
may have experienced ‘more than one’ high-level exposure to the irritant, since in
many industries accidental spills are relatively common [10]. The term RADS was
progressively replaced by ‘irritant-induced asthma’ (IIA), but this acronym remains
often cited because of its high recognition value.
Only few studies are available to characterize the histopathology of the bronchial wall of patients with IIA. In general, nonspecific inflammatory infiltrates
(lymphocytes, plasma cells, neutrophils) are present, often with thickening of the
connective tissue [9, 37]. Gautrin et al. [38] described desquamation of bronchial
epithelium and squamous cell metaplasia, as well as fibrosis of the bronchial
wall and increased basement membrane thickness in five workers, 2 years after
repeated exposures to high concentrations of chlorine. In biopsies from a patient
exposed to chlorine, Lemière et al. [39] saw considerable epithelial desquamation
with inflammatory exudates and swelling of the subepithelial space 2 weeks after
the exposure; 2 months later, biopsies showed regeneration of the epithelium by
basal cells and still a pronounced inflammatory infiltrate that recovered after
steroid treatment [39]. Chan-Yeung et al. [40] were the first to show the presence
of eosinophils in the bronchial inflammatory infiltrate of patients that suffered
from ‘gassings’ in a pulp mill. These scarce data on histopathology suggest that
inflammatory characteristics of IIA may be less extensive than in immunologically
mediated OA, but this picture is nonspecific and cannot serve to make a definite
diagnosis of IIA.
Data on possible mechanisms inducing IIA are only speculative. Brooks et al. [9]
proposed a ‘big bang’ theory in which the initial irritant exposure causes significant
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epithelial damage associated with activation of the non-adrenergic, non-cholinergic
(NANC) nerve system via axon reflexes, with the onset of a neurogenic inflammation through the release of neuropeptide transmitters such as Substance P and neurokinins. This epithelial damage can lead to release of relaxing factors, along with
non specific macrophage and mast cell activation, which release proinflammatory
cytokines and other mediators such as leukotrienes B4 and C4 [41], resulting in epithelial cell desquamation, smooth muscle cell hypertrophy and matrix degranulation
[1, 38].
There is increasing evidence that chronic exposure to lower levels of irritants
can also induce a form of OA [9, 42]. The fact that lower levels of irritant exposure
could initiate asthma requires consideration of mechanisms other than airway damage alone to induce the asthma attack. It was noteworthy that 87% of the individuals that developed IIA in a less sudden way were atopic. One theory is that atopic
persons elicit a different response to irritant exposure [42]. Another theory suggests
an augmentation of the sensitivity to respiratory allergens by irritants, possibly
through disruption of the epithelial barrier [43]. However, so far, no evidence exists
to prove these theories. Moreover, the very existence of the entity of “not so sudden
IIA” is currently disputed.
Acute inhalation of irritant chemicals may lead to persisting upper airway symptoms, with complaints from nose, sinuses and larynx. This entity has been described
by Meggs et al. [44] as ‘reactive upper airway dysfunction syndrome’ (RUDS), by
analogy with its asthmatic counterpart. These authors studied patients with chronic
rhinitis after a chlorine dioxide exposure. Even less is known about mechanisms
causing these upper airway problems after irritant exposure, but they are thought
to be similar to those causing IIA, and neurogenic inflammation in response to epithelial damage is probably the key factor. Publications on RUDS or irritant-induced
rhinitis are even rarer than those of RADS and irritant-induced asthma, so that the
incidence and prevalence of this condition are even more obscure.
Animal models
In comparison with occupational diseases caused by inhaling mineral dusts or
fibers, there has not been a lot of experimental research using laboratory animals
to unravel the pathogenesis of OA. Yet, animal models can have a valuable role in
gaining more information on the complex immunological and pathophysiological
mechanisms involved in the development of allergies and asthma. At present a considerable part of what we know about the pathogenesis of asthma has been derived
from animal experiments [45]. However, this research has been conducted mostly
with HMW agents, especially ovalbumin, and only few research groups have investigated chemical-induced asthma.
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Mechanisms of occupational asthma caused by low-molecular-weight chemicals
Although no mouse model is currently able to mimic the full range of clinical
manifestations that constitute human asthma, a number of models are available that
reproduce several features that characterize its most common phenotypes. Nevertheless, important differences in airway development and morphology exist between
humans and mice, thereby preventing the direct extrapolation of data between the
species. Mouse airways have fewer airway generations and do not contain smooth
muscle bundles. As a consequence, mouse models cannot be considered a surrogate
for human asthma but they must be viewed as an opportunity to generate and test
hypotheses in a relatively simple controlled system [46, 47].
The most common mouse strain used in this research area is the BALB/c mice,
which exhibits a genetically determined tendency to develop Th2-biased immune
responses. However, less Th2-prone mouse strains can also develop an asthmalike response. Several protocols for the induction of asthma have been developed
and published employing a wide variety of antigens, application routes, doses and
sequences as well as readouts [48].
Stimulation of the cholinergic and sensory nerves
The chemicals are initially recognized by APC present in the airways. Once the
chemical is taken up, the APC get activated and release proinflammatory signals that
not only influence the status of other cells of the immune system but also stimulate
sensory pathways that activate the central nervous system. The vagus nerve has been
proposed as an immune-to-brain pathway and it has been suggested that acetylcholine may modulate the airway immune response. Cholinergic mechanisms represent
the predominant constrictor neural pathway, of which airway hyperresponsiveness
(AHR), an important phenotype of asthma, is a good example [49].
Scheerens et al. [50] found an involvement of sensory neuropeptides in TDIinduced AHR in mouse airways. Sensory nerves are found in abundance around
pulmonary blood vessels and in the epithelium of the trachea and bronchi of many
species. Scheerens et al. found that tachykinins (substance P and neurokinin A)
are involved in the effector phase of TDI-induced AHR when mice were sensitized (via epicutaneous application) and intranasally challenged. Furthermore, the
tachykinins did not seem to act directly on the tracheal smooth muscle but via
the activation of other cells (T lymphocytes and mast cells). Beside the effect on
AHR, substance P also plays a role in the influx of inflammatory cells, particularly
neutrophils [51].
It is also important to mention that many reactive chemicals, including sensitizers such as diisocyanates, have strong irritant properties when they are used in
high concentrations. The airway responses to these irritants result partly also from
reflexes mediated by sensory and autonomic nerve fibers in the airways [51].
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Lung function measurements
A change in breathing pattern immediately after airway exposure has been documented in various mouse models of chemical-induced asthma. Pauluhn et al.
[52–54] described a decrease in breathing frequency after nose-only exposure to
diphenylmethane-4,4’-diisocyanate (MDI), 1,6-hexamethylene diisocyanate (HDI)
and TMA in sensitized guinea pigs and rats. Vanoirbeek et al. [55–57] showed differences in enhanced pause (Penh), a parameter representing bronchoconstriction,
immediately after intranasal challenge with TDI or TMA.
Nonspecific AHR is generally measured 1 or 2 days after challenging the mice
with a specific antigen. Many research groups focusing on chemical-induced asthma
have found an increase in AHR to methacholine [52, 55–62]. Scheerens et al. [50]
were the first to find in vitro AHR after carbachol exposure. As mentioned above,
they found that sensory neuropeptides played an important role. Furthermore,
Matheson et al. [63] and Tarkowski et al. [56] showed the absence of AHR in
athymic mice and severe combined immunodeficiency (SCID) mice, respectively,
suggesting an important function for T-lymphocytes in these models. Herrick et al.
[64] and Matheson et al. [59] showed that both CD4+ and CD8+ lymphocytes are
crucial in mouse models of asthma caused by HDI and MDI, respectively.
Airway inflammation
In comparison with asthma induced by HMW agents, where eosinophils and
lymphocytes are the characteristic cell types present in the bronchoalveolar lavage
(BAL) fluid, asthma induced by LMW agents has been associated with an influx
of mainly neutrophils and eosinophils [50, 55, 56, 62, 63, 65]. The type of inflammation is also highly dependent on the duration of exposure and the route of challenge. For example, Vanoirbeek et al. [55, 60] found mainly an influx of neutrophils
when TDI-dermally sensitized mice received a single intranasal challenge with TDI,
whereas De Vooght et al. [62] found an influx of neutrophils as well as eosinophils,
using the same dermal sensitization protocol, but altering the challenge route from
intranasal instillation to oropharyngeal aspiration.
Herrick et al. [66] used HDI conjugated to mouse serum albumin (MSA) to challenge their mice. Using this complex they found an inflammation in the BAL that
correlated with the phenotype of atopic asthma, i.e., an influx of eosinophils and
lymphocytes.
The influx of inflammatory cells is mediated by several cytokines and chemokines. Increases of Th2 (IL-4, IL-5, IL-13) and Th1 (IFN-G) cytokines was found in
homogenates of lung tissue [59, 66]. Macrophage inflammatory protein 2 (MIP-2),
a chemokine for neutrophils in mice, was found to be increased [56]. IL-1 also seems
to be an important mediator in chemical-induced asthma. IL-1 stimulates the release
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of IL-5, which is important for the recruitment and activation of eosinophils, and
induces the production of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), important for leukocyte recruitment [67].
Matrix metalloproteinase 9 (MMP-9) is the major proteinase that induces bronchial
remodeling in asthma. In addition, MMP-9 as well as vascular endothelial growth
factor (VEGF) induce the migration of eosinophils and neutrophils [65, 68]. Tumor
necrosis factor A (TNF-A) is a major initiator and propagator of airway inflammation and promotes the migration of DC [69]. In addition, through their effect on
airway inflammation, IL-1, MMP-9, VEGF and TNF-A, lead to AHR.
So far, most mouse models are based on an “acute” form of OA. The main focus
has been on the inflammation found in the BAL, while structural changes of the lung
and airways tissue have not often been investigated. Some degree of peribronchial
and perivascular inflammation, epithelial shedding, mucus hypersecretion by proliferation of the goblet cells and some perivascular remodeling have been described in
the lungs of mice with diisocyanate-induced OA [62, 66, 70].
Immunoglobulins
Both increases in specific antibodies, as well as total serum immunoglobulins (IgE
and IgG) have been described in diisocyanate-treated mice. However, a consistent
observation in isocyanate-induced OA is the absence of any meaningful association
between these serological findings and the presence or absence of airway responses,
or with airway inflammation [71].
Scheerens et al. [72] found that by altering the exposure time and/or cumulative dosage, TDI is capable of inducing different immunological reactions. When
sensitizing the animals longer they were able to find specific IgE and IgG in serum,
compared to a shorter protocol. Matheson et al. [58] and Herrick et al. [64] also
found specific immunoglobulins (IgG) after a low-level subchronic exposure to
TDI and exposure to HDI-MSA, respectively. Vanoirbeek et al. found increases in
total serum IgE, IgG1 and IgG2a in TDI and TMA asthmatic mice. In isocyanateinduced OA it is known that immune responses can emerge from IgE-dependent
or non-IgE-dependent mechanisms, but the functional meaning of this in animal
models remains unclear and probably non-essential. It is known that immunological sensitization to LMW asthmagens is often lifelong. The only ‘remedy’ to
avoid the symptoms of OA is removal from the exposure place [73]. If asthmatic
workers can avoid contact with the causal asthmagen, improvement of AHR can
occur [74]. This was confirmed in the TDI mouse model of Vanoirbeek et al. [60].
In this set of experiments, the researchers increased the time between sensitization
and intranasal challenge, resulting in a decrease of the AHR and airway inflammation, regardless of the high concentrations of IgE, IgG1 and IgG2a in the serum of
TDI-treated mice. This is further confirmation that immunoglobulins are present
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in chemical-induced asthma; however, their role in the pathophysiology of OA is
uncertain at best.
Controversial issues
Neutrophils and OA
In the pathophysiology of OA due to LMW asthmagens, discussion often occurs
concerning the presence and the role of neutrophils, as the main BAL inflammatory
cell. In non-OA the presence of neutrophils is considered a marker of disease severity [75]; however, this is not yet established in OA. Moscato et al. [31] found that
a positive response to the specific inhalation challenge (SIC) of persulfate salts was
correlated with an increased sputum eosinophilia, while in symptomatic workers
with a negative response to the SIC a neutrophilic inflammation was predominant.
Park et al. [76] found a predominant neutrophilic inflammation in TDI-induced
asthmatics, which was linked to IL-8, a chemokine involved in neutrophil attraction. This dichotomy between a predominant BAL neutrophil or eosinophil inflammation is also found in animal model of OA [52, 58, 60, 62, 66, 70]. Probably, the
nature of the pulmonary inflammation in asthma is heavily dependent on the time
course of the disease, the pattern of the exposure and individual susceptibility factors [28, 31, 77].
The skin and OA
In OA it is generally assumed that exposure to the respiratory tract is the key route
and site for the initiation of the immune responses. Accordingly, research, regulation
and prevention focus almost exclusively on airborne exposures. However, despite
reductions in workplace respiratory exposures, isocyanate asthma continues to
occur, and this has prompted a focus on skin as a route of exposure [78, 79]. Evidence that skin exposure may increase risk for isocyanate sensitization and asthma
in humans is mainly derived from case reports and limited cross-sectional studies
[78, 80, 81]. Recently, isocyanate skin exposure has been documented using newly
developed qualitative and quantitative methodologies in car body shop workers and
painters. The authors found substantial skin exposure to isocyanates, while these
workers were occupied in a setting where airborne exposure was minimal, and
despite the use of standard personal protective equipment such as gloves [81–83].
Several animal models have shown convincingly that skin exposure to chemical sensitizers (predominantly isocyanates, but also anhydrides) can induce systemic sensitization, which may result in asthma-like respiratory responses when the animal is
later challenged via the airways [56, 64, 70]. These murine studies suggest that the
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occurrence of respiratory responses depend on several factors related to both the
nature and timing of the sensitization and that of the challenge [55, 60, 61].
Specific antibodies and OA
Controversy still exists regarding the role of specific antibodies in asthma induced
by LMW asthmagens. While some LMW asthmagens (e.g., complex platinum salts
and TMA) consistently produce specific IgE antibodies, other LMW asthmagens,
most notably TDI and western red cedar (plicatic acid), do not. For example, in
TDI-asthmatics specific IgE antibodies are only found in 0–50% of exposed workers [84]. It has been suggested that sensitization to isocyanates can be achieved via
other immunological mechanisms, such as direct T cell activation [20]. On the other
hand, it has been suggested that IgE antibodies go undetected for largely technical
and methodological reasons [4]. A technical limitation was shown by Son et al.
[85], who showed that the variable results in the presence of specific IgE antibodies to TDI in serum of exposed workers depended on the heterogeneous binding of
specific IgE of a TDI-asthmatic to an antigenic determinant of TDI-human serum
albumin conjugate in vitro. This binding can differ between one individual and
another. So, it remains unclear whether IgE-mediated responses contribute to the
development of asthmatic symptoms in workers exposed to TDI. Not only the role
of specific IgE responses, but also the role of specific IgG is under debate. After TDI
exposure, specific serum IgG can persist for many years [26]. Although the sensitivity for measuring specific IgG in serum of TDI-induced asthmatics is higher than
specific IgE, the sensitivity is still poor. Therefore, it is rather suggested that IgG
could be used to monitor exposure to diisocyanates, rather than act as a marker of
sensitization [26, 86].
Mechanisms of IIA
Little or no experimental research has been conducted to clarify the mechanisms
of persistent airway hyperreactivity that occurs in some victims of a single acute
inhalation injury. Morris et al. [87] showed that capsaicin treatment could reverse
the respiratory effects of chlorine gas inhalation in mice, suggesting an important
role of sensory receptor channels on the nerve endings in the respiratory mucosa.
Martin et al. [88] described histological changes in the airways and increases in
bronchial reactivity to methacholine in mice after a single inhalation of chlorine
gas, but their experiments did not go beyond 7 days. Further publications by the
same group point to acute immunological changes and airway remodeling [89, 90],
but these studies do not yet help us understanding the determinants of RADS in
humans. Both Guo et al. [91] and Venglarik et al. [92] have shown a reduction in
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bronchial transepithelial electric resistance in response to hypochlorite exposure.
However, no phenotypic responses have been linked to this finding so far. The possible role of repeated exposures to low concentrations of occupational chemical
irritants in the causation of asthma has been studied even less. An ozone-induced
asthma model has been set up by the group of Pichavant et al. [93], in which iNKT
cells and IL-17 seem to be important disease markers. Furthermore, findings related
to co-exposures of antigens with ozone, cigarette smoke or diesel exhaust particles,
involving DC priming, GM-CSF and leading to up-regulation of Th2 related cytokines, may contribute to understanding the mechanisms of IIA [94–98].
Transient receptor potential channels and IIA
As already mentioned, neural activation causes pain and irritation, neurogenic
inflammation, mucus secretion, and reflex responses such as cough, sneezing, and
bronchoconstriction [99, 100]. Recently, members of the transient receptor potential (TRP) superfamily of ion channels have been proposed to play a key role in the
response of sensory neurons to inflammatory mediators [99, 101, 102]. The two
major proinflammatory TRP ion channels in sensory neurons are TRPV1, the capsaicin receptor, and TRPA1, activated by mustard oil [99, 103]. Agonists of TRPV1
and TRPA1, such as capsaicin, acrolein, diisocyanates or chlorine, are potent tussive
agents and have been associated with allergic and occupational asthma and RADS
[101, 104–106]. In TRPA1–/– KO mice or when a TRPA1 antagonist is used in an
animal model, inflammation and acute airway responses to chemical exposure are
substantially decreased [104–107]. These data suggest that activation of TRPA1
and TRPV1 on airway sensory fiber terminals by hazardous irritants could evoke
noxious respiratory sensation, sensitization of respiratory reflexes, and the local
release of proinflammatory neuropeptides, which can lead (in the long term) to OA
or IIA [99].
Putative mechanism of action
Combining all data from human and mice, sketches have been made trying to give
an overview of the mechanisms of OA induced by LMW asthmagens. Keeping in
mind that the skin is a relevant site for initiation of sensitization, Figure 1A gives an
overview of the sequential events that presumably take place after dermal contact
with LMW sensitizers that could lead to sensitization. When applied on the skin,
LMW sensitizers bind to proteins (e.g., keratine) [16] and form hapten-protein
complexes. Langerhans cells in the epidermis internalize these hapten-protein complexes. The activated Langerhans cells mature and migrate to the draining lymph
nodes, while processing the protein complex. The processed protein complex is
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Mechanisms of occupational asthma caused by low-molecular-weight chemicals
Figure 1.
(A) Hypothetical scheme to describe the dermal sensitization phase. (B) Hypothetical model
of the immunopathogenesis of asthma induced by LMW agents. These two models give an
overview of findings in the literature. APC, antigen presenting cell; GM-CSF, granulocytemacrophage colony stimulating factor IFN, interferon; IgE, immunoglobulin E; IL, interleukin;
KC, keratinocyte; LC, Langerhans cells; LMW, low-molecular-weight; MHC, major histocompatibility complex; MIP, macrophage inflammatory protein; MMP, matrix metalloproteinase;
MCP, monocyte chemotactic protein; TNF, tumor necrosis factor; VEGF, vascular endothelial
growth factor. Figure adapted and modified from [71, 108, 109].
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Vanessa De Vooght et al.
presented to naïve T cells via the MHC, hereby activating the T cells. T cells differentiate to both memory Th1 (via IL-12) and Th2 (via IL-4) cells. IL-4 and IL-13
released from Th2 cells also stimulate B cells to produce IgE, which is released into
the blood. Activated and memory T cells (Th1 and Th2) and B cells migrate from
the local draining lymph nodes to the peripheral tissues and the blood [108, 109].
Subsequently, Figure 1B illustrates the possible pathogenic cascade leading to
LMW asthmagen-induced OA. The primary event in this process, after the LMW
asthmagens have reached the respiratory mucosa, is the conjugation of asthmagens
with proteins in the airways, such as albumin and possibly other epithelial cell proteins (e.g., tubulin on top of the cilia and actin) [16, 17, 110]. The antigenic epitopes
resulting from the interaction of LMW asthmagens with the proteins will lead to
airway inflammation, but this remains poorly characterized. Probably the antigenic
epitopes of the protein-hapten complex will be presented to the Th1, Th2 and B
cells by APC. IgE from the B cells will cross-link the protein-hapten complex with
mast cells that release their mediators (e.g., histamine) and cause an acute asthmatic
response. Moreover, via the T cells several cytokines and chemokines get released,
which mediate several cellular responses and activate neutrophils, eosinophils and
basophils, leading to a chronic state of asthma [20, 71, 79, 109, 111].
Admittedly, in this schematic overview we only focused on the well-known allergic pathway of OA and we did not included the neurogenic mechanisms of action
(TRP-receptors, substance P, neurokinines), which recently have been suggested
to play a (important) role in both IIA and OA. Multiple questions remain to be
answered, including the determination of relevant routes of exposure, better characterization of the immune response, the inflammatory cells involved and mediators responsible for LMW asthmagen-induced sensitization and OA, along with the
identification of the genetic factors that regulate airway inflammation. Although
the mouse models of LMW asthmagen-induced asthma share features common
with human chemical-induced OA, none of them perfectly replicates real-life human
exposures or the disease in humans. Nevertheless, good models are important to
protect workers from compounds that act as respiratory sensitizers, which can lead
to asthma after repeated exposures.
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162
Asthma-like diseases in agriculture
Torben Sigsgaard 1, Øyvind Omland 1,2 and Peter S. Thorne 3
1
School of Public Health, Department of Environmental and Occupational Medicine,
Aarhus University, Denmark
2
Department of Occupational and Environmental Medicine Aalborg, Aarhus University
Hospital, Denmark
3
Environmental Health Sciences Research Center, University of Iowa, Iowa City, USA
Abstract
Although many studies on asthma have been conducted in farming populations, no longitudinal
studies have been published so far. Smoking, work in pig barns, and crop farming together with
exposure to endotoxin and quaternary ammonium have been described as environmental risk
factors for self-reported asthma and/or wheeze in cross-sectional studies. The prevalence of selfreported asthma has been found to range from 0.7% in female greenhouse workers to 21% in Danish smoking female farming students. Exposure in farming is diverse, but dominated by organic
dust containing high amounts of compounds known to trigger the innate immune system. This is
confirmed by a wide range of human experimentation where naïve persons have been introduced
to swine confinements. Cross-sectional data suggest a protective effect of farming on allergy. However, differences in the diagnostic procedure and the predominantly wheezy asthma type in farming
concomitant with a lower rate of allergic asthma makes the comparison difficult. Furthermore,
healthy worker selection, misclassification, age differences, difference in time of study and small
study populations, resulting in low statistical power, might be factors explaining the findings. Welldesigned longitudinal studies of the incidence of carefully defined phenotypes of asthma and risk
factors are needed to clarify the risk of asthma, or wheezy phenotypes related to farming.
Introduction
Agricultural work represents a major hazard for respiratory disease. Both asthma
and chronic obstructive pulmonary disease (COPD) have been reported related to
farming [1, 2]. While farm workers have inhalation exposures to pesticides, diesel
particulates and toxic vapors, the major exposure is organic dust composed of
mould hyphal fragments and spores, bacteria, endotoxins, glucans, mite allergens,
animal-derived material like dander, hair, bristle, urine, and feces together with
animal feeds. The vast majority of studies of asthma in agriculture have been performed without agent-specific exposure assessment, and only a few studies have
included exposure assessment as part of the design.
Occupational Asthma, edited by Torben Sigsgaard and Dick Heederik
© 2010 Birkhäuser / Springer Basel
163
Torben Sigsgaard, Øyvind Omland and Peter S. Thorne
Respiratory symptoms in agriculture
Prevalent work-related lung symptoms in farming are wheeze, cough, and dyspnea,
and these are often much more frequent than among control subjects or among
random population samples [3–6]. However, these symptoms are nonspecific and
might reflect acute lung irritation as well as symptoms associated with respiratory
disease. The clinical picture of obstructive lung diseases in agriculture is diverse with
major symptoms of asthma, COPD (or both), bronchial hyperresponsiveness and
increased yearly loss in FEV1 associated with few or any respiratory symptoms. The
designation of asthma-like syndrome in agriculture has been introduced from studies mainly in the U.S. of highly exposed swine confinement workers [6, 7]. However,
farming is probably one of the exposure situations with the most diverse range of
asthma phenotypes [8], ranging from clearly IgE-dependent asthma with eosinophilic influx related to allergen exposure (e.g., enzymes or cow dander or horse hair)
to non-IgE-dependent asthma dominated by neutrophilic influx and wheezing [9].
The neutrophilic phenotype is characterized by a self-limited inflammatory event
that might or might not involve persistent airway hyperresponsiveness [10]. The
end stage presents as respiratory symptoms, bronchial hyperresponsiveness, and
accelerated lung function decline in the absence of sensitization against swine feed
and food allergens [10].
These features have been confounding research into asthma in farming, and only
recently has the discussion of asthma phenotypes been addressed by the scientific
community [11–13].
Studies of asthma-like symptoms in agriculture
In this chapter we apply the term “asthma-like diseases” as a questionnaire-defined
outcome of “asthma” or “asthma-like symptoms” in epidemiological studies in
agriculture. No longitudinal studies on incidence of asthma in farming populations
have been published and rates of asthma incidence associated with farming are
based on data from surveillance systems for occupational diseases including asthma.
These systems are mainly made for insurance and compensation purposes for the
workforce [14]. In the available data sources there are differences in the definition
of occupational asthma (OA) between countries and heterogeneity in classification
of occupation. Some surveillance programs are without information as to whether
farming is classified as an occupation. Due to weakness in coverage and case ascertainment there might, therefore, be a general tendency in underreporting of asthma
in farming. From those surveillance systems in which data from farming occupation
are present, the incidence figures from Finland [14] are by far the highest. The mean
annual incidence rate was 174 cases/106 employed workers and the mean annual
incidence rate for male farmers was 1200 and for female farmers 1910. These high
164
Asthma-like diseases in agriculture
figures in the farming population are probably due to the custom in the Finnish
farming to brush their cows daily. Data from Germany [15] arise from the worker
compensation system. The annual mean incidence rate was 51 cases/106 employed
workers, and in farmers the figure was 113 cases/106 employed workers. Swedish surveillance data are based on self-reported asthma and here the mean annual
incidence rate was 80 cases /106 employed workers, while in male farmers and in
female farmers it was 170 and 203 cases/106 employed workers, respectively [16].
By far the lowest data on incidence of OA has been reported from USA, the state of
Michigan [17]. These data arise from physicians’ reports, compensation claims and
hospitals. The annual mean incidence rate was 30 cases/106 employed workers and
in agricultural production the figure was 3 cases/106 employed workers.
More than 30 cross-sectional studies of the prevalence of asthma-like symptoms
in agriculture have been published, and in 18 the prevalence data have been related
to the prevalence in a non-exposed control group (Tab. 1) or associated with the
prevalence in the general population or a random sample of the general population
(Tab. 2).
The mean prevalence of asthma in a representative sample of 1685 Danish
farmers [3] was 7.7%, lowest (3.6%) among farmers aged 30–49 and highest
(11.8%) among farmers aged 50–69 years. The prevalence of asthma was highest among pig farmers (10.9%). Age (OR 5.8, 95% CI 2.8–12.2) and pig farming (OR 2.0, 95% CI 2.0–3.5) were risk factors for self-reported asthma. The
prevalence of asthma among farmers was the same as in a representative sample
of the Danish populations aged 30–49 years, but significantly higher among farmers aged 50–69 years (OR 2.25, p < 0.001). The prevalence of current asthma in
1706 farmers from New Zealand [18] was high (11.8%), although lower than the
prevalence of asthma measured in the general population (15%). Female farmers
had an increased risk for asthma (OR 1.8, 95% CI 1.3–2.5). High prevalence of
asthma (18.3%) was also found among 904 randomly selected Swiss farmers [19],
but no difference was observed in the prevalence of asthma attack between farmers (2.1%) and a random sample of the Swiss population (3.1%). Current (OR
2.14, 95% CI 1.43–3.19) and former smoking (OR 2.05, 95% CI 1.34–3.14) were
risk factors for asthma. The prevalence of asthma was 2.8% (95% CI 2.4–3.2)
in a random sample of 7496 European farmers from Denmark, Northern Germany, Switzerland and Spain [20]. In an American rural population, farmers had
an asthma prevalence of 9.8% in females and 3.8% in males: the OR for ‘ever
farmed’ versus ‘never farmed’ was 0.77 (95% CI 0.48–1.24) [21]. The prevalence
of asthma among the farmers aged 20–44 years (1.3%, 95% CI 0.9–1.7) was
significantly lower than in an age-matched sample of the general European population (ECRHS) (3.2%, 95% CI 2.9–3.9; p = 0.001). In Norway [22] the asthma
prevalence among a random sample of 2106 farmers was 4.0%, significantly
lower than among a random sample of 351 rural (5.7%) and 727 urban (7.6%)
controls. Recent data from The Netherlands [23] have found a significantly lower
165
166
1988
1999
2001
2001
2002
2004
2007
[3]
[18]
[19]
[20]
[21]
[22]
[23]
Netherlands
Norway
USA
Denmark,
Germany,
Sweden, Spain
Switzerland
New Zealand
Denmark
Country
1205 conv. 593
organic 2679s
2106 + 1078s
574 + 1056
7496
904
1706
1685
No. of subjects
5.2 conv.
2.9 organic
4.0
3.8 males
9.5 females
1.3
18.3
11.8
7.7
11.8 age 50–69
3.6 age 30–49
Asthma prevalence
among farmers
Sign. Lower than controls
Sign lower than controls, both
atopic and non-atopic
Lower for males
N.D. for females
Sign lower than controls
N.D.
N.D.
l subjects aged 50–69 OR 2.25
N.D. for aged 30–49
Prevalence in agriculture vs
general population
s, sample of the general population; conv., conventional farmers; organic, organic farmers; N.D., no difference.
Year
Ref.
Smoking OR 1.1
Smoking OR 2.1
Female OR 1.8
Pig farming OR 2.0
Environmental risk
factors
Table 1. Cross-sectional studies of the prevalence of asthma-like symptoms in agriculture and in the general population.
Torben Sigsgaard, Øyvind Omland and Peter S. Thorne
1997
1999
2001
2001
1999
1998
1993
1998
2005
2005
2007
[24]
[25]
[26]
[27]
[28]
[29]
[30]
[31]
[32]
[33]
[34]
NZ
US
Gr
South Africa
Croatia
Fr
NL
Croatia
Croatia
DK
DK
Country
4288 + 1328c
1140 + 10132c
122 + 100c
134 + 122c
167 + 81c
265 + 149c
239 + 311c
814 + 635c
236 + 165c
1901 + 407c
1691 + 407c
No. of subjects
c, controls; Sign., significantly; N.D., no difference.
Year
Ref.
14.3–15.6
7.73
6.7
4–13
0.7–6.3
5.3
5.9
0.7–7.7
0.7–7.7
5.4–21.0
Smo 11.3/13.2
Non sm 5.3/5.9
Asthma prevalence
Sign. lower
Sign. higher
N.D.
Sign. higher
N.D.
N.D.
N.D.
N.D.
N.D.
N.D.
N.D.
Prevalence in agriculture
vs controls
Table 2. Cross-sectional studies of the prevalence of asthma-like symptoms in agriculture and in controls.
Farming OR 1.54
Quaternary
ammonium OR 9.4
Smoking OR 1.7
Smoking sign l
Environmental risk
factors
Asthma-like diseases in agriculture
167
Torben Sigsgaard, Øyvind Omland and Peter S. Thorne
prevalence of asthma-like symptoms among both conventional farmer (5.2%) and
organic farmers (3.9%) compared a random sample of the general population
(7.6%).
In a Danish study of 1901 farming students, of whom 210 were females, and in
407 rural controls the prevalence of asthma-like symptoms was between 5.4% and
21%, but no difference was observed between farming students and controls [25].
Asthma in the mother (OR 3.4, 95% CI 2.1–5.7), sex [OR (males) 0.5, 95% CI
0.3–0.8], and smoking (OR 1.7, 95% CI 1.2–2.4) were factors significantly associated with asthma. Data of the prevalence of OA from two studies in farm workers
in Croatia [26, 27] showed no differences (0–7.7%) among the 236 livestock and
the 814 crop farm workers and food packing controls, for either smokers or non
smokers. Vogelzang et al. [35] found in a study of 239 pig farmers and 311 rural
controls the same prevalence of asthma in the two groups (5.9%) versus (5.5%). In
pig farmers the use of disinfectants (quaternary ammonium compounds) (OR 9.4,
95% CI 1.6–57.2) and aspects of disinfecting procedure were associated with the
prevalence of asthma. Atopy was significantly less prevalent in pig farmers (4.6%)
compared to controls (14.6%) and pig farmers had significantly fewer symptoms
of allergy in childhood (9.9%) than controls (17.2%). Atopy in childhood was
strongly associated with the prevalence of asthma symptoms (OR 4.1, 95% CI
2.2–7.7). Cross-sectional data from a French study of 265 dairy farmers and 149
non-exposed controls [29] revealed the same cumulative prevalence of self-reported
asthma and of current asthma in farmers and in controls; 5.3% and 1.5%, respectively, versus 3.4% and 1.3%. Prevalence data of asthma in non-animal farming
occupation has been analyzed among 135 female and 32 male greenhouse workers
[30]. No significant increase in the prevalence of asthma was observed compared to
non-exposed 51 female and 30 male controls, either for males (6.3% vs 0%) or for
females (0.7% vs 0%). Among 134 South African poultry workers, the prevalence
of asthma was significantly higher (4–11%) than among 122 controls [31], while
the prevalence of asthma was elevated but not significantly higher (6.7%) among
120 grape farmers from Crete compared to 100 controls (2.0%) [32]. Among 1140
male New York dairy farmers [33], the prevalence of asthma was 7.73% and significantly higher than among 10 132 male non-farmers (5.03%). New Zealand data
involving 4288 farmers and 1328 controls found a significantly lower prevalence of
“asthma ever” among dairy farmers (14.8%) and sheep and beef farmers (15.6%)
compared to non-farming controls (23.3%) [18].
Exposures in agriculture
Exposures in agriculture are varied and dependent upon whether the operation is
producing row crops, livestock or fruits, nuts and vegetables. Common exposures
may include diesel exhaust, fuel vapors, pesticides and disinfectants, and welding
168
Asthma-like diseases in agriculture
fumes. Crop production generally includes exposures to fertilizers such as anhydrous
ammonia, while livestock production usually is associated with exposures to hydrogen sulfide, ammonia, and a multitude of odorous sulfur- and nitrogen-containing
vapors [36]. Among the most potent odorous compounds are the organic acids,
including acetic, butyric, caproic, propionic, and valeric acids; nitrogen-containing
compounds such as ammonia, methyl amines, methyl pyrazines, skatoles and
indoles; and sulfur-containing compounds such as hydrogen sulfide and dimethyl
sulfide [37]. These odors smell like rotten eggs (hydrogen sulfide, dimethyl sulfide)
or rancid butter (butyric acid, isobutyric acid) or have a putrid-fecal smell (indole,
skatole, valeric and isovaleric acid).
Organic dust is a catchall term for the array of bioaerosols that arise in agriculture and downstream manufacturing that produces value-added food products,
animal feed, seeds, ethanol, biomass, and compost. Toxicologically important components of organic dust include pathogenic microorganisms; microbial, plant and
animal allergens; and microbial-associated molecular patterns (MAMPs) including
endotoxin, B-glucans, and CpG DNA (Fig. 1).
Figure 1.
The role of pathogen-associated molecular patterns (MAMPs) and pattern recognition receptors in organic dust exposure.
169
Torben Sigsgaard, Øyvind Omland and Peter S. Thorne
Pathogenic bioaerosols from livestock facilities are responsible for cases of infectious disease that extend beyond zoonoses typically seen only among farmers and
veterinarians. The use of antimicrobials as growth promotants in livestock production has led to increased antimicrobial resistance of bacteria in swine and calf
barn effluents to medically important antibiotics. In the U.S. over 300 scientific,
medical, and advocacy organizations have called for legislation to eliminate the
non-therapeutic use of antimicrobial agents (Pew Commission on Industrial Farm
Animal Production 2008). Methicillin-resistant Staphylococcus aureus (MRSA) is
an emerging concern that has been linked to excessive use of antibiotics [38]. Multidrug-resistant culturable bacteria were measured in bioaerosols 150 m downwind
of a swine operation with the finding that over 80% of the organisms were resistant
to two or more classes of antibiotics [39]. Another infectious disease concern is that
conditions inside industrialized livestock facilities will give rise to a pandemic strain
of influenza [40]. Past outbreaks in Asia and recent cases in Southern California
demonstrate the significance of this threat (CDC 2009). The two cases of infection
with swine influenza A (H1N1) virus in the San Diego area occurred in unrelated
children living in adjacent counties neither of whom had contact with pigs. The
influenza virus they carried was resistant to two antiviral agents used to treat flu
and contained gene segments that had not previously been observed in humans
or swine. It is presumed that they both contracted influenza via human-to-human
transmission.
Allergenic components of organic dust include thermophilic bacteria such as Saccharopolyspora rectivirgula and Thermoactinomyces vulgaris that are responsible
for allergic alveolitis (also called hypersensitivity pneumonitis). Grain storage mites,
animal danders, plant pollens, enzymes and possibly antibiotics added to animal feed
can act as allergens, leading to allergic rhinitis and allergic asthma in some workers.
The constituents of organic dust posing the greatest health burden are arguably the MAMPs of which endotoxin has been studied the most. Endotoxin is an
amphiphilic molecule of bacterial cell walls that induces innate immune responses in
an amplifying cascade [41], leading to recruitment of neutrophils and macrophages
to the lung. Endotoxin exposures in agriculture have been extensively studied and
representative exposure data are presented in Table 3.
In recent work, Spaan et al. [42] have carefully evaluated methods for analyzing
endotoxin with an eye toward recommending a fully specified standard method.
Identical inhalable dust samples were collected to investigate the effects of filter type
(glass fiber or Teflon), transport conditions (with/without desiccant), sample storage
(–20° or 4°C), extraction solution [pyrogen-free water (PFW) or PFW plus 0.05%
Tween 20], extract storage (–20° or 4°C), and assay solution (PFW or PFW plus
0.05% Tween 20) on endotoxin concentration [42]. No differences in endotoxin
concentration were attributable to transport conditions or storage temperature of
extracts. Extraction in PFW plus 0.05% Tween 20 resulted in 2.1-fold higher estimated endotoxin concentrations. Sampling on glass-fiber filters and storage of sam-
170
Personal – total
Personal – respirable
Personal – inhalable
Area – inhalable
Personal – total
Personal – inhalable
Grain elevators
Potato processing
Soybean harvesting (closed tractors)
Agricultural seed processing industry
GM, geometric mean.
Personal – inhalable
Area – inhalable
Animal feed manufacturers
Other agriculture
100
1800
56
9–102
1–000
195
68
32
2860
83.2
410
410
530
79
12–285
19
Smit et al. 2006 [107]
Roy & Thorne, 2003 [106]
Zock et al. 1998 [105]
Schwartz et al. 1995 [104]
Smid et al. 1992 [103]
Thorne et al. 1997 [102]
Saito et al. 2009 [44]
1340
5000
35
150
1000
9000
2000
81
200
81
120
118
198
191
Area – total
Area – inhalable
Thorne et al. 2009 [100]
Duchaine et al. 2001 [101]
Thorne et al.1997 [100]
Preller et al. 1995 [99]
Kullman et al. 1998 [98]
3100
3250
3927
8290
920
64
17
GM endotoxin
Reference
concentration, EU/m3
40
30
Poultry
Area – inhalable
Swine conventional confinements
Swine hoop barns
21
81
350
194
216
No. of
samples
Chicken
Dairy
Cattle feedlot
Horse
Swine
Turkey
Area – total
Area – total
Swine
Personal – inhalable
Swine
Swine
Personal – inhalable
Area – respirable
Air sample
Dairy
Livestock operations
Operation
Table 3. Airborne endotoxin exposure values in agricultural operations.
Asthma-like diseases in agriculture
171
Torben Sigsgaard, Øyvind Omland and Peter S. Thorne
ples in the freezer produced 1.3-fold and 1.1-fold higher endotoxin concentrations,
respectively. This study found that there were important gaps in the specification
of the CEN protocol and suggested parameters needed to fully specify a standardized protocol. In a second manuscript, Spaan et al. [43] compared four extraction
media: PFW, PFW-Tween 20, PFW-Tris, and PFW-triethylamine-phosphate (TAP)
to determine which performed best in the LAL assay and extracted the most endotoxin. PFW-Tris produced similar results to the PFW alone. PFW-TAP showed lower
yields and a deviant calibration curve. Tween in the extraction medium resulted in
significantly higher endotoxin yields from all dust types, independent of the effect
of Tween in the assay. Among these four media, only Tween reproducibly enhanced
the efficiency of endotoxin extraction from airborne dust samples.
A recent study evaluated endotoxin exposure assessment in six types of livestock
operations using four types of air samplers in two regions of the U.S. [44]. This
study demonstrated excellent agreement in 906 samples between analysis of endotoxin using the kinetic chromogenic LAL assay and the recombinant factor C assay
with a correlation coefficient of r = 0.91 (p < 0.01) and the relationship overlaying
the line of identity.
The other MAMP for which there has been exposure assessment in agriculture,
albeit limited, is fungal B-glucans. These polysaccharide components of fungal cell
walls can be measured using the Factor G pathway of the LAL assay [45] or by
single-antibody ELISA [46, 47] or sandwich ELISA [48, 49]. Most studies that have
measured glucans were focused on mold exposures in the indoor environment.
Human experiments
The first systematic studies of farming responses in humans were performed at
the University of Iowa using extracts of corn dust (CDE) and LPS [50–53]. This
research initiated the human experimental approach to the basic mechanism of
the innate immune system on acute respiratory inflammation. The results showed
that neutrophils increased in nasal lavage from 17 × 103 to 40 × 103 cells/ml in
grain workers exposed to 2372 EU LPS/m3 compared to postal workers exposed
to 4 EU/m3. However, no association was found to the LPS concentration among
grain workers [52]. A study with an inhalation of aerosolized CDE confirmed the
inflammation related to CDE. This initiated a series of experiments on the kinetics
of the human and the mouse reaction to CDE. The response in humans was shown
to start immediately after inhalation and last 2 days for bronchoconstriction, 4 days
for neutrophilic influx, and 7 days for the increase in proinflammatory cytokines
IL-1B IL-6 and IL-8. These changes were mirrored in the mouse model, although
within a shorter period, leading to the conclusion that the mouse model would be
an appropriate model to study grain dust-induced inflammation [53]. No increase
in the reaction was found in atopic subjects compared to non-atopic subjects. In a
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study of grain workers with bronchial hyperresponsiveness (BHR), it was shown
that those workers with BHR had a greater decline in FEV1 compared to “normal”
workers. Surprisingly, this was not reflected in any differences in the bronchoalveolar lavage (BAL) fluid sampled 4 h after the exposure to 0.16 Mg/kg nebulized
endotoxin in CDE [52].
Swine
In farming, the first studies to suggest that LPS is the causative agent were from
the Sweden and the Netherlands, and showed that endotoxin exposure was related
to symptoms and FEV1 in pig farmers [54, 55]. These initial studies have been followed by a range of quasi experiments in which the farming environment has been
used to study the effect of the innate immune system. A group from Stockholm has
been especially active in this field. Their work has elucidated the time course of the
inflammatory events occurring after an acute exposure to organic dust [56–61].
In one study, this group showed that the acute changes they had observed in nonfarmers were attenuated or totally abolished in healthy farmers adapted to the
environment, and speculated on which mechanisms might be responsible for such
an adaptive mechanism [62].
In a study of farmers experiencing asthma-like symptoms during work in swine
confinement buildings and controls, it was shown that inflammatory responses in a
work-like environment with low concentrations of LPS (0.5 Mg/m3) and dust (4 mg/
m3) are similar to responses found after exposure to higher concentrations often
used in experimental situations. Acute neutrophilic inflammatory responses and
increases in BAL IL-6 and IL-8 were found; however, this response was attenuated
among farmers who had already experienced asthma-like symptoms during exposure in swine confinement buildings [63]. In the same experiment, differences in
complement response were found that may compensate for variation in the inflammatory response [64].
Laboratory animal-exposure studies
Inhalation experiments using guinea pigs, rats and mice have been extremely informative for identifying inflammatory agents in organic dust, establishing their potency
and elucidating their mechanistic underpinnings. Studies in the 1980s in guinea pigs
investigated the pulmonary effects of cotton dust and demonstrated that the effects
on breathing patterns and production of fever were due to the endotoxin content. In
more recent work, mice have been the animal model of choice due to the availability
of inbred strains and knockout mice with specific characteristics or gene deletions
[65]. Murine studies in the 1990s demonstrated that endotoxin was the principal
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Torben Sigsgaard, Øyvind Omland and Peter S. Thorne
inflammatory agent in extracts of organic dust recovered from the air handling
system of grain elevators handling corn (CDE). Inhalation-exposed mice developed
a dose-dependent influx of monocytes and neutrophils to the lung and increases in
TNF-A and IL-6 [36, 53, 66]. C3H/Hej mice bearing a mutation in the TLR4 gene
exhibited a blunted response to a semi-purified endotoxin preparation [67] with a
1000-fold lower neutrophilic response than C3HeBFej normoresponsive mice [68].
Endotoxin exposure studies in mice of different strains have demonstrated a
wide range of inflammatory responsiveness [69]. Among inbred strains without
recognized genetic defects in endotoxin response genes, there was a 3-fold range
of neutrophilic response between the least responsive to the strongest responder.
Among mutant strains there was a 50-fold range. These studies used the Sigma E.
coli 0111:B4 preparation of endotoxin which is believed to contain other MAMPs.
Recent murine studies [41], informed by previous in vitro studies [70–72], have
shown that responsiveness to highly purified endotoxin requires functional CD14,
MD-2 and TLR4 [41]. MD-2 knockout mice do not mount an inflammatory response
when exposed to purified endotoxin, but the response can be reconstituted if the same
amount of endotoxin is delivered to the lung as a monomeric complex of endotoxin
and recombinant MD-2 [41]. Lung exposure to mutant penta-acylated endotoxin
produces a blunted inflammatory response as compared with treatment with wildtype, hexa-acylated endotoxin. Treatment of CD14 knockout mice with endotoxin is
also blunted but can be restored by treating with endotoxin:MD-2 complex.
Simultaneous exposures to endotoxin and allergens in lab animals have produced conflicting results. Studies using ovalbumin as the allergen found that concomitant endotoxin exposure suppressed the development of allergy [73, 74], while
studies that used environmental allergens such as Aspergillus flavus, cat dander or
cockroach allergen observed amplification of antibody production and pulmonary
hypersensitivity [75–77]. In a neonatal exposure model, mice inhaling endotoxin
(300 EU/day) and cockroach allergen (10 ng/day) on days 2–21 of life demonstrated
increased pulmonary inflammation, increased total and specific IgE production, and
lung remodeling compared to mice that inhaled endotoxin alone or allergen alone
[77]. The inflammatory response measured in lung lavage fluid was marked by an
influx of neutrophils and cytokines (TNF-A, IL-6, MIP-1A, KC, RANTES, G-CSF,
and IL-12p40) that were 4–18-fold higher than observed in the mice treated with
endotoxin only. These data illustrate that the complex mixtures we encounter in
complex settings such as agricultural environments can be synergistic, and therefore
need to be studied as mixtures rather than one compound at a time.
The modification of disease by farming exposure
It has been known for some time that being brought up at a farm decreases the
allergic manifestations among the children concomitantly with an increased risk
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of wheezing among the children associated to high concentrations of endotoxin
[78–80], with an effect still detectable during young adulthood [81]. Recently, it has
been shown that this effect is still observable even later in adulthood. Studies in a
rural community in Norway [82] have shown that farmers have a lower prevalence
of atopic diseases including asthma. However, they have a higher prevalence of
inflammatory wheeze associated with endotoxin exposure.
Studies of agricultural workers from New Zealand [83] and The Netherlands
[23, 84] have demonstrated that being brought up on a farm has a bearing on the
subsequent reaction to agricultural exposures. This was most clearly demonstrated
in a recent study of Dutch agricultural workers, where Smit et al. [84] showed that
the place of upbringing was an effect modifier for the association between wheeze
and endotoxin exposure (Fig. 2).
Figure 2.
The association between hay fever, wheezing prevalence and endotoxin exposure stratified
for place of upbringing. From [84].
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Torben Sigsgaard, Øyvind Omland and Peter S. Thorne
Susceptibility factors
There is a great variability in the individual response to organic dusts. Almost 50%
of Caucasians respond to LPS exposure [85], and people with A-1-antitrypsin deficiency are hyperresponsive to organic dust exposure [86, 87].
Atopy has been proposed as one of the factors associated with increased susceptibility to organic dusts. The evidence is scarce; however, people with mild asthma or
with BHR do have an increased reactivity towards LPS exposure [88, 89] and garbage
workers with OA of the neutrophil type are not able to recruit PMNs in the nose
as readily as workers without OA after nasal installation of LPS [90]. Furthermore,
atopic subjects seem to react differently to LPS in the whole blood assay [91].
A few studies have shown A-1-antitrypsin to be a risk factor for respiratory
symptoms among workers exposed to organic dusts such as cotton dust and grain
dust [86, 92]. CD14 polymorphisms have been studied as a risk factor for OA;
however, the data are conflicting regarding the possible effect of such polymorphisms, which might relate to differences in the techniques used for LPS analysis
or to different study designs. The first polymorphism related to LPS susceptibility
was demonstrated in a study by Arbour et al. [93] who found that a few co-segregating mutations in the TLR4 gene were responsible for LPS hyporesponsiveness in
humans. The allele frequency was around 8% in the Iowa population, and, hence, it
cannot explain the high number of non-responders reported by Castellan et al. [85]
in the cotton-exposure study. TLR4 polymorphisms have not been associated with
asthma in studies of populations [94], and it has not been possible to demonstrate
any association with the protective effect on atopy that is seen among farmers’ children [95]. TLR4 is one factor in a complex and long response pathway, which may
accumulate mutations in other components of the pathway [96].
In Germany, a study of atopy among children from farms and non-farms has
demonstrated that the protective effect of being raised on a farm was abolished
if the children had a mutation in the TLR2 gene. Although TLR2 was previously
thought to play a role in LPS recognition, other receptors like B-glucans and peptidoglycans are now considered as candidates for agents responsible for the protection against atopy, such as that observed among the farmers’ children [95].
Very recently, a polymorphism in TLR10 has been shown to be a risk factor for
asthma, consistent within different samples of the American population. Whether
this will have any implications for persons exposed to organic dust is presently
unknown, since the ligand for TLR10 is not known [97].
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183
Allergen and irritant exposure and exposure-response
relationships
Dick Heederik and Gert Doekes
Division of Environmental Epidemiology, Institute for Risk Assessment Sciences,
Utrecht University, Utrecht, The Netherlands
Abstract
Exposure to allergens and irritants is a complex phenomenon. Especially the particulate nature
of many natural allergens in combination with the low exposure creates remarkable phenomena.
Many allergens appear to be potent sensitizers in the nanograms per cubic meter of air range.
Evidence exists that workers can be sensitized even after exposure to a low number of particles.
With exposure in the low nanogram range, the respiratory tract is exposed to distinct exposure
quanta of a few particles, which lead to high local concentrations of allergenic molecules. With
gaseous exposure, a more equal exposure over the large surface area of the respiratory organ is
to be expected. These phenomena may have mechanistic and biological implications, but certainly
determine exposure assessment approaches, the interpretation of exposure measurements and the
evaluation of exposure-response relationships.
Introduction
Exposure-response relationships are considered important because they point
towards options for prevention. Exposure is a complex phenomenon and varies
considerably over time and space. Characterizing exposure for assessing relationships with asthma occurrence in epidemiological studies requires understanding of
exposure phenomena. These phenomena in their turn determine the approach in the
analysis to a large extent. When all this is taken in consideration, exposure-response
relationships can be analyzed. Many examples exist of exposure-response relationships for low- (LMW) and high- (HMW) molecular-weight agents, mainly from
industry-based studies in which the exposure has been measured in quantitative
terms. Some of these examples are presented and discussed in this chapter. General
population studies with less detailed exposure information are not discussed. Recent
developments such as the use of exposure-response information in risk assessment
is only briefly covered here.
Occupational Asthma, edited by Torben Sigsgaard and Dick Heederik
© 2010 Birkhäuser / Springer Basel
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Allergens and irritants
An allergen is a non-parasitic/non-pathogenic/non-infectious antigen capable of
inducing immune-mediated hypersensitivity reactions in sensitized hosts. The preceding ‘sensitization’ consists of allergen-specific immune responses to a previous
exposure, upon which specific T cells and antibodies have been produced – as a
rule, without any observable symptomatic adverse health effects. During secondary
exposures of the sensitized host, the specific antibodies and/or T cells recruit and
activate inflammatory cells and mechanisms that normally should protect against
harmful pathogens. For normally harmless allergens like grass pollen, cat saliva or
dog skin flakes, however, the costs of these inflammatory reactions – adverse health
effects, and allergic symptoms – heavily outweigh the benefits of immune protection. “Atopic” or type I hypersensitivity refers to allergy based on specific IgE and
so-called Th2-type sensitization. Since this is the best studied type of allergy associated with work-related respiratory disease, this chapter further focuses exclusively
on type I allergens and IgE-mediated allergy.
Allergens causing type I-mediated (‘atopic’) immunological asthma can be both
LMW and HMW sensitizers of which more than 250 have been identified. LMW
sensitizers are often synthetic industrial chemicals such as isocyanates, acid anhydrides, metals and metal salts, but also natural substances such as plicatic acid from
western red cedar wood. LMW sensitizers are supposed to react with and to bind
covalently to human proteins in the respiratory tract mucosa, and to function as
major epitopes in the thus-produced immunogenic ‘hapten-carrier’ complexes. The
epitope specificity of the produced antibodies in the serum of the sensitized worker
can be demonstrated by showing their binding in diagnostic tests with the LMW
hapten (like isocyanate) coupled to a range of different carriers.
HMW sensitizers are naturally occurring water-soluble proteins in the 10–60kDa molecular mass range that in a hydrophilic environment, like the respiratory
mucosa, are readily released, e.g., from skin scales, plant fibers, pollen grains, and
other tissue matrices. Some allergenic products contain only one or a few allergens.
For instance, commercially graded fungal A-amylase contains the active enzyme,
with a molecular mass between 51 and 54 kDa, and some other allergenic compounds of 25–27 kDa and 40 kDa, probably enzyme fragments or fungal products
[1]. Wheat flour has been shown to contain more than 100 allergenic molecules,
of which 40 have been identified [2]. For such complex products like wheat, latex,
etc., the exposure assessment should either be based on measuring one single marker
molecule, using highly specific monoclonal or polyclonal antibodies, or on characterizing and measuring the whole mixture of antigenic/allergenic proteins with a
pool or mixture of polyclonal antibodies [3]. Both approaches have been used and
so far have resulted in allergen assays with strongly concordant results [4, 5].
The situation may be analogous for some LMW sensitizers like isocyanates,
where exposure occurs to a mixture of the monomer and monomer-derived oli-
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gomers. The most recent studies have measured several monomers and oligomer
molecules, and expressed exposure in total isocyanate concentration [6–8]. This
is a simplified way of combining exposure to a range of molecules with probably
different allergenic potency into one metric. Theoretically it would be possible to
weigh the relative contribution of an individual molecule to a mixture by its allergenic potency. However, this information is only available for a limited number of
isocyanate molecules tested in experimental animal studies [9, 10] and is not possible practically.
Irritants are agents for which the effects do not depend on preceding specific
sensitization. They can thus provoke acute and transient narrowing of the airways
at first exposure of an individual, and may do so through a variety of non-immunological mechanisms such as mast cell mediator release, and interaction with sensory
nerve endings in bronchial epithelium or receptors in smooth muscle. Irritants may
have stronger effects in individuals who are bronchially hyperresponsive. A common incited acute response to irritants should be distinguished from the induction
of reactive airways dysfunction syndrome (RADS). While the same chemicals that
incite transient airway narrowing can also cause RADS, induction of the latter
seems the result of extremely high peak exposures to chemical irritants such as
chlorine compounds, ammonia, diisocyanates, etc. Irritant exposure is of interest
because it may also interact with allergen exposure in the sense that the risk for
developing allergy and asthma may be modified. Examples are diesel exposure and
sensitization to common allergens [11] and exposure to disinfectants in farming and
atopy and bronchial hyperresponsiveness [12].
Exposure and exposure routes
Exposure is defined as contact between a target, in the context of this chapter a
human, and a chemical, biological or physical agent in an environmental carrier
medium [13]. For occupational asthma (OA) contact between the respiratory organ,
and air as a carrier containing allergens or irritant gases or particulates, is the most
relevant exposure. Recent indications suggest that dermal exposure might also
play a role. Uptake of an agent is determined by the concentration in the medium
(concentration in the air), the uptake of the medium (ventilation, inhalation), and
clearance from the lung. The dose of an agent is the amount that enters the target,
in this case the respiratory mucosa and underlying tissues. The amount that enters
the upper and lower airways is, therefore, not always the relevant amount, because
for instance a large fraction of very small particles – in the 10–100 nm range – and
inert, non-soluble gases may also be directly exhaled, thus leading to a lower effective dose. So dose should be defined as the amount that is absorbed by (in case of
gases), or deposited on (in case of particulates) the respiratory mucosa. One should
consider that the definition of ‘dose’ may depend on the mechanism of the studied
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health effect: whether it only requires interaction with cells and molecules in the
mucosa, or also needs to migrate through the respiratory basal membrane to submucosal tissue, or even the surrounding capillaries or lymph nodes. It should be
realized that most information about particle deposition is based on research with
inert radiolabeled particulates. Very little is known about the role of deposition,
clearance and retention of allergenic or irritant particulates. Particle deposition is
size and shape dependent and differs for different regions of the respiratory organ.
For near spherical particulates, behavior is well described by the aerodynamic diameter. The aerodynamic diameter is an expression of the aerodynamic behavior of a
particle (for a perfect sphere with unit density, the diameter equals the aerodynamic
diameter). Generally speaking, larger particulates deposit in the nasopharyngeal
region (including nasopharynx, oral passages, and larynx) by sedimentation and
impaction. Retention times in this region are short, usually between minutes to
hours [14]. In the tracheo-bronchial tree, which includes the trachea, bronchi and
bronchioli, particles are deposited by impaction in the upper part and by sedimentation in the lower part. Non-soluble particles are usually cleared within 1 day by
the ciliated airways and most are swallowed. In the alveolar zone, particles deposit
by sedimentation and diffusion, and are removed very slowly by cellular clearance
mechanisms with clearance times from months to years. Different size fractions have
been defined which can penetrate different regions of the respiratory organ [15]. For
OA research, the inhalable dust fraction (50% cut-off at 10 Mm) is the most important dust fraction, and is defined as those particles which can penetrate the human
respiratory organ. Some literature exists that indicates that deposition in the nasal
region can induce reactions distal from the nose, so larger particulates may be relevant for effects lower in the airways [16]. Traditionally, occupational hygiene studies focused on pneumoconiosis and monitoring programs commonly measured the
fraction of respirable dust particles (50% cut-off at 4.25 Mm) of which the majority
can penetrate the alveolar region. This fraction is more relevant for toxicants for
which uptake through the alveoli can take place, and for dusts which cause pneumoconiosis. These particles are smaller than most of those in the inhalable fraction.
The respirable fraction underestimates the exposure to larger particulates for which
deposition in both the upper and lower airways may also be of primary importance,
like most of the known allergen-carrying particles. It should be further emphasized
that the boundaries between the various particle fractions and the regions where
these are deposited are not sharp. Thus, while the majority of allergen particles,
e.g., of 10–20 Mm diameter, will be deposited in the upper airways, a substantial
proportions may reach the lower respiratory tract and induce not only rhinitis but
also asthma symptoms.
Dermal exposure is a considerably less explored field in exposure assessment for
OA. There is clear animal evidence showing that LMW sensitizers, like isocyanates,
may induce sensitization after dermal exposure, with subsequent inhalation challenges resulting in asthma-like responses [17]. Several lines of evidence support a
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similar role for human isocyanate skin exposure, namely, that dermal exposure may
contribute to the development of isocyanate asthma by inducing systemic sensitization [18]. More research is needed in this field to develop and improve dermalexposure assessment methods for sensitizing agents [19, 20], since objective and
reproducible methods are lacking and it is unclear how dermal exposure should be
measured in a biologically relevant way for OA. Dermal exposure is usually measured by hand washing methods, dermal patches, or by analyzing gloves, but none
of these approaches are completely satisfactory.
Variability of exposure and exposure patterns
Temporal aspects of exposure are considered important, e.g., is the exposure
relatively constant and at the same level, or are there fluctuations or possibly even
sharp and large increases over time (peaks)? Many allergen exposed workers are
exposed to a pattern of high peaks over a working day. Measurements with continuously registering devices have shown that bakers are exposed to peaks of flour or
enzymes when they empty bags, dust dough, or clean the bakery [21]. These peaks
occur when flour particles become airborne because of physical forces, but since
they are relatively large (aerodynamic diameter 5–15 Mm and often even larger [22,
23]) they will reside in the air for only a brief period of time. As a result, even the
highest peaks last for a maximum of only several minutes [21], and between these
task-related high peaks the exposure will be very low. This exposure pattern is typical for many situations with exposure to HMW and non-gaseous LMW sensitizers,
because relatively large particulates are involved, and peak exposures are usually
the consequence of regularly performed daily tasks. Very high dust and allergen
exposures, however, may also occur infrequently, e.g., due to repair or cleaning
activities of damaged or neglected equipment or storage sites. Examples are environments such as laboratory animal facilities with exposure to rat and mouse urinary
proteins, the farm environment with exposure to allergens and microbial agents
such as endotoxins, health care settings with exposure to latex. The baker’s work
is typically cyclic, with a daily repeated pattern of exposure peaks, and the average
exposure over the day is therefore relatively similar from day to day. Thus, within
a day the exposure is highly variable because of the sequence of peaks and low
background levels, but between days the differences are relatively small. Among
laboratory animals workers day-to-day variation in exposure may be much larger.
Typical high-exposure tasks are the handling of living animals and the cleaning of
cages and removal of cage bedding. For workers routinely involved in cage cleaning there may be regular temporal patterns of high exposure, and also for animal
caretakers there may be daily tasks, e.g., feeding, leading to more or less cyclic
exposure patterns. Researchers performing animal experiments may, however, often
have days or even weeks with practically no allergen exposure. Exposure assessment
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in this job category therefore strongly relies on combinations of allergen measurements and careful monitoring – using diaries or questionnaires – of performed tasks.
Allergen-exposure levels in farming have hardly been studied, but may a priori be
expected to show a very large variation. In animal farming many job tasks show
daily patterns – like feeding and milking – and on many days the average daily
exposure may thus be relatively constant. Other potentially high-exposure activities, however, like emptying and cleaning of stables and barns, occur regularly but
with much lower frequency over the year. In crop farming the exposure to plant or
microbial allergens will be strongly associated typical season-related activities, like
harvesting. Although no data on allergen exposure are available, results for airborne
dust and endotoxin levels in farming and various agricultural industries suggest
that it indeed shows very pronounced within-day but also day-to-day and seasonal
variation [24, 25]. Similar patterns may also occur for LMW sensitizers such as diisocyanates used in spray painting. In industrial spray painting, the within-day variation may be high but daily exposure patterns relatively constant, whereas in many
small companies – notably car repair shops – the day-to-day variation may also be
very large depending on the actual work available. Apart from that, there may be
other reasons for incidental peak exposure. Spray painters usually work in highly
controlled environments such as spray booths with exhaust ventilation systems. As
a result, the exposure is often below the limit of detection but high exposures occur
because they regularly spray outside the booth for small repairs or during formulation of paint, cleaning of equipment and because of spills [6].
Physical and chemical aspects of airborne allergen exposure
It is useful to conceptualize how exposure to allergens occurs. Large measurement
series in the baking industry, as part of an exposure-response study on fungal
A-amylase [26], showed that workers with a high exposure were exposed to timeweighted average levels of fungal A-amylase between 5 and as high as 100 ng/m3.
These data were obtained with full-shift (8 hour) measurements, and thus represent
daily averages. Moderately exposed individuals were exposed to levels between 0.5
and 5 ng/m3, but in this category more than 70% of the measurements were below
the limit of detection [26]. Workers in the high-exposure category were mainly
dough makers working with pure enzyme formulations. Workers with “moderate”
exposure levels did not handle pure enzyme but batches of cereal flours to which the
enzyme had been added – either elsewhere in the bakery or in the flour-supplying
industry. Since amylase is added in only milligrams quantities per kilogram flour (a
1/106 ratio on the basis of weight), the amylase exposure at a worksite between 1
and 5 mg/m3 flour dust exposure – common for dough makers – would be around
1–5 ng/m3, which agrees well with the observed average amylase levels. It is, however, less easy to understand why for the majority of measurements in this exposure
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Allergen and irritant exposure and exposure-response relationships
category the amylase levels remained under the limit of detection. A likely explanation might be the particulate nature of the amylase, which is added as solid powder
to the cereal flours, with as consequence a highly heterodisperse distribution of
airborne amylase. Since these allergen exposure characteristics may have important consequences for exposure-assessment strategies, and for the interpretation of
exposure-sensitization relations, they are discussed below in some more detail. Both
wheat and airborne amylase allergens have been mainly found in airborne particles
with aerodynamic diameter between 5 and 15 Mm [22, 26]. Assuming a spherical
shape and density of 1–1.5 g/cm3, one may estimate their mass to range between
0.04 and 2 ng. Thus, if amylase is added to flours as a 50–100% pure enzyme powder, each milligram of the resulting ‘mixture’ consists of approximately 1–10 million
wheat flour, but only 1–10 amylase particles; when the mixture becomes airborne,
a moderate dust exposure of 1 mg/m3 would mean that workers will be exposed
to a very limited number of amylase particles per cubic meter. Due to the random
particle distribution at such low numbers, however, airborne measurements – with
usually close to 1 m3 air sampled per filter (on the basis of a sampler sampling 2–3 l/
min) for personal full-shift air samples – will inevitably show a high coefficient of
variation (CV) and potentially many samples with an allergen content below the
detection limit. In fact, with on average only a handful of particles per air sample,
there is a substantial risk of having no amylase particle at all in a sample, and
this may be one of the reasons that even at moderate average levels many samples
remain negative when tested for the presence of amylase.
The heterodisperse nature of some airborne allergens can be confirmed by direct
staining methods, like the HALOgen procedure [27] in which allergen-specific antibodies are used to visualize the allergen molecules released from a particle trapped
on a filter or adhesive tape. Application on personal inhalable dust sample from
baker’s work environment clearly confirmed that only very few of the many dust
particles on a filter showed the presence of A-amylase (Fig. 1).
The airborne dust composition described here may be exceptional, with all allergenic (amylase) activity concentrated in a few particles per cubic meter, surrounded
by ~106 other non-allergenic particles – or particles with other allergenic specificity
like wheat proteins in this particular case. For 100% pure enzyme powder the number of allergen molecules per particle is, given a molecular mass of around 52 kDa
for fungal A-amylase, extremely high and varies between 109 and 1010 per particle,
depending on its exact size. So amylase exposure appears to occur in the form of
a limited number of ‘allergen quanta’ consisting of particles with a large number
of allergenic molecules per particle. For other allergens the situation might be less
extreme, but the same principles may be applied, e.g., to animal dander particles,
or fecal particles from house or storage mites. Although the latter contain many
other molecules, it has been shown that each mite fecal particle may contain up to
2.5–5% (w/w) of the major allergen Der p1, which, assuming a particle diameter of
approximately 20 Mm and a molecular mass of 24 000, implicates ‘allergen quanta’
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Dick Heederik and Gert Doekes
Figure 1.
HALOgen staining of A-amylase in an airborne bakery dust sample (courtesy J Bogdanovic,
IRAS UU). The sample shown was taken during a 30-minute period when a bakery worker
was dusting dough with enriched flour. Two amylase containing particulates are visible. The
whole filter contains not more than 25 particulates, indicating that a bakery worker, handling
enriched flour may be exposed to a very low number of amylase containing particulates per
day.
of no less than 108–109 Der p1 molecules per particle [28]. Parallels also exist for
exposure to pollen. Grass pollen exposure ranges from a few to several hundreds
of pollen per cubic meter measured as long-term average concentration [29, 30].
When exposed to water, pollen grains may rupture at the single germinal aperture,
releasing around 700 granules of less than 3 Mm in diameter from each grain [31].
This leads to several hundreds to thousands of particulates per air samples [29, 30,
32], but still a relatively low number considering the number of allergen molecules
involved.
This is in clear contrast to a spray painter working with a diisocyanate monomer
or a monomer oligomer mixture of, for instance, 1,6-hexamethylene diisocyanate
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Allergen and irritant exposure and exposure-response relationships
(HDI). Monomer exposure will to a large extent be gaseous because of the vapor
pressure of HDI. This implies that even at low exposure levels, a large number of
molecules will be inhaled by, and dispersed across, the respiratory organ. Diisocyanate exposure to oligomers of HDI, however, occurs in the form of small aerosol
droplets, likely with limited number of particulates containing many allergenic
molecules with free isocyanate groups. There are indications from experimental animal studies that gaseous monomer exposure is more potent at eliciting respiratory
responses than particulate exposure, and that differences in particle size distribution
are also associated with a quantitatively different response [10, 33]. Many of these
differences may be due to a different deposition pattern for different particle size
distributions, leading to differences in dose in specific zones of the respiratory organ.
For mixed particulate and vapor exposure, the vapor molecules may be adsorbed to
the surface of the particle and penetrate deeper into the airways and lungs than in
the case of gaseous exposure only. This may also contribute to a qualitatively and
quantitatively different response.
It is not clear what the biological implications of localized high exposure are.
It may be important to discuss the question separately for the allergic sensitization
process and for the induction of symptoms in sensitized subjects. What distribution and what levels are sufficient to lead to a high sensitization risk? Results from
dermal sensitization studies suggest that a few antigen-presenting dendritic cells
encountering many molecules may induce a more vigorous response than many
dendritic cells encountering only a few molecules [17]. Thus, the focal presentation of a very small number of allergenic molecules concentrated on a few cells
may represent an exposure pattern that results in a major risk for sensitization. It
therefore seems important to consider the nature of the exposure pattern in terms
of aggregation phase (gaseous, particulate), particle distribution, and time pattern
of exposure (peaks) [34]. Incidental (peak) exposure to a very limited number of
particulates seems associated with only a mildly elevated risk for sensitization risk
[26, 35]. Specific IgE titers against fungal A-amylase appeared to be low in workers with moderate exposures to fungal amylase [26]. However, workers involved in
handling pure enzyme can be exposed more frequently to short exposure peaks of
up to a few hundred milligram per cubic meter of pure enzyme for a few minutes
[21]. Over a working day this will average out to a lower level, in the Mg/m3 range,
and for longer periods – weeks to months – the average levels may be far below
1 Mg/m3. Thus, the increased sensitization risk observed at average exposure levels in
the ng/m3 range may in fact be the result of incidental ‘sensitizing events’ when the
exposure increases suddenly but very briefly to 100–1000-fold higher levels.
The phenomena described above may also play a role in LMW sensitizer exposure. Spray painters are now more often exposed to oligomers than simply just
gaseous monomers. Oligomer exposure is more likely to occur in the form of particulates. Exposure is very often below the limit of detection and is highly variable
when above this limit and differs from moment to moment by more than a factor
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Dick Heederik and Gert Doekes
10–1000. Spray painters often seem to face very low exposure, but during intensive
spraying, or mixing of paint, brief periods of high exposure occur [6].
Exposure-response relationships
Studying exposure-response relationships for asthma is complex. The manifestation of the disease is variable and this complicates measurement of the presence of
disease. The threshold concentration for elicitation of an allergic airway reaction in
sensitized individuals is generally assumed to be lower than the threshold concentration to induce sensitization [17, 36]. Direct evidence for this observation is limited
because elicitation levels for symptoms and other signs are poorly documented both
in experimental and observational studies. It is only recently that allergen exposure
data have been applied for exposure-response modeling using observational data
from human populations. Some sensitizers, especially LMW ones like diisocyanates
and acid anhydrides, may also have irritant properties. Irritating effects may occur
in parallel at lower levels in atopic individuals who have been sensitized to common allergens, but not sensitized to the occupational allergen. Thus, although the
evidence is not always very strong, different exposure-response relationships may be
anticipated for different subgroups of workers. Theoretically, the slope and intercept
of the exposure-response relationship might differ between individuals in the same
workplace according to the mechanism of disease provocation (and therefore host
factors) [36].
A clear definition of the actual health outcome studied is crucial for any statement regarding exposure-response relationships, and this is particularly true for
the development of asthmatic disease. A simple model for the pathogenesis of OA
induced by HMW sensitizers is usually represented as follows (Fig. 2): exposure
leads to a series of events – sensitization, and development of an inflammatory
response, which is accompanied by symptoms, bronchial hyperresponsiveness, airflow variability, etc. When exposure is continued, chronic changes and severe airflow impairment might occur. This process can develop rapidly and, as a result, it
seems likely that workers may try to influence their exposure when they develop
symptoms by migrating to jobs with lower exposure or leave the workforce (healthy
worker effect). Examples of exposure-response relationships for the first step, sensitization, have been described for many allergens. For some LMW sensitizers exposure-response relationships have been observed. One prospective study included 163
previously unexposed workers with exposure to epoxy resins containing organic
anhydrides: hexahydrophtalic anhydride (HHPA), methyl hexahydrophtalic anhydride (MHHPA), and methyltetrahydrophtalic anhydride (MTHPA) [38]. These
workers were followed for, on average, 32 months (1–105 months). The levels of
organic acid anhydrides in air and of specific IgE and IgG in serum were monitored
repeatedly. The mean combined organic acid anhydride exposure was 15.4 Mg/m3
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Allergen and irritant exposure and exposure-response relationships
Figure 2.
Etiological model for the development of occupational asthma (after [37]).
(range < 1–189 Mg/m3). An exposure-response relationship was clearly demonstrated
for the incidence of sensitization with increasing exposure. Specific IgE was demonstrated by 21 (13%) subjects with a mean induction time of 8.8 (1–35 months).
The sensitization incidence was 4.1/1000 person months at risk. Atopics had a more
than fivefold elevated sensitization risk compared to non-atopics.
Several other authors have also described exposure-response relationships for
various organic acid anhydrides [39–41]. Similar observations have been found for
some other LMW sensitizers such as platinum salts [42, 43] and isocyanates [44],
although the available evidence is more limited than for organic acid anhydrides and
the HMW sensitizers discussed in the following section. Early studies already gave
some indications that exposure-response relationships could be observed for HMW
sensitizers. Musk et al. [45] showed that bakery workers with a “high dust rank”
were more often sensitized against one or more bakery allergens compared to work-
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ers with a low dust rank. The dust classification was validated with total dust measurement. More recent studies in bakers used dust sampling instead of the – from
an immunological viewpoint – more valid allergen measurement [46]. These studies
have probably been successful because wheat allergen levels in flour dust correlate
reasonably with dust levels [26, 47]. For most other HMW allergens, however, there
often is no such direct correlation between airborne dust and allergen levels, because
dust and allergen levels do not always share the same sources and determinants of
exposure. For these allergens, exposure-response relationships could be explored
only after immunoassays became available for sensitive and specific measurement
of these allergens [3]. Overviews of available exposure-response studies [17, 48,
49] show that several allergens, e.g., rat urinary proteins and fungal A-amylase,
appear to be potent allergens, and are associated with increased sensitization rates
at low exposure levels in the nanogram or even picogram per cubic meter range for
as little as a few hours per week [26, 49]. Allergens like wheat proteins seem less
potent and sensitization risk increases in the low microgram per cubic meter range
[50]. A longitudinal exposure-response study in bakers has confirmed the results of
the cross-sectional studies on fungal A-amylase and wheat allergen exposure [51].
Clear-cut exposure-response relationships in humans have as yet not been observed
for latex proteins, since few epidemiological studies on latex sensitization have
yet been conducted in which exposure was assessed with the use of latex-specific
immunoassays.
Effect modification of exposure-response relationships
In most of the above-mentioned studies, modification of the exposure-response
relationship by atopy has been considered. The most direct and usually optimal
approach to assess effect modification by atopy is a stratified analysis, in which
intercept and slope of the exposure-response relations are determined separately for
atopic and non-atopic subpopulations (‘strata’). In most of the studies following
that approach, the slope of the exposure-response relationship is generally steeper
for atopics compared to non-atopics.
One should realize that the association between exposure and sensitization is
biologically specific in the sense that specific antibodies are formed against the
allergen. This implies that there is only one determinant of sensitization in a strict
epidemiological sense, because a confounder is required to be a determinant of the
endpoint under study. Confounding cannot occur because there is only one determinant, and a confounder is by definition another determinant.
Further along the causal chain, other endpoints can also be studied. Several studies have explored the relationship between symptoms and exposure. This requires a
specific strategy because the respiratory or work-related symptoms may not exclusively be caused by exposure to one specific allergen, but may also be associated
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Allergen and irritant exposure and exposure-response relationships
with other factors in the work environment, or to non-occupational factors like
smoking, exposures at home, or outdoor exposures. Thus, confounding by several
other causes may occur here. If one wants to explore the association between exposure and symptoms, one needs to further stratify for specific sensitization because
this is expected to be a strong modifier of risk for symptoms elicited by the specific
allergen exposure. This is clearly illustrated by the example below (Tab. 1).
Table 1. Exposure-response relationship for work-related respiratory symptoms and wheat
allergen exposure stratified by specific IgE sensitization to wheat (from [50]).
Work-related symptoms
n/N
%
Sensitization to wheat
Low exposed
1/7
14.3
Intermediated exposed
4/10
40.0
High exposed
10/19
52.6
Low exposed
17/110
15.5
Intermediate exposed
21/97
21.6
High exposed
25/103
24.3
Not sensitized to wheat
IgE-sensitized workers had a considerably higher risk of developing symptoms
at intermediate and high exposure levels than non-sensitized workers, and the
exposure-response relationship in this subgroup is much steeper in the wheatsensitized subgroup. Interestingly, additional analyses suggested that among nonwheat-sensitized workers, atopics (workers with IgE to common allergens like
house dust mites and grass pollen, but not to occupational allergens) also had a
somewhat higher risk than non-atopics. Atopic individuals are known to respond
more often and possibly at lower exposure levels to any irritant or allergenic stimuli.
The underlying mechanism is not associated with specific sensitization to a common
allergen, but more likely an indirect association with bronchial hyperresponsiveness
or some irritant mechanism. Similar observations are available for other allergens
and from longitudinal studies [52, 53]. Some studies have shown findings indicating
that sensitization does not always precede symptoms in people exposed to known
allergens [54]. Mechanisms than other sensitization probably explain the occurrence
of their symptoms. Thus, several exposure-response relationships exist with different underlying biological mechanisms. If one does not distinguish these different
modifiers in the analysis, exposure-response relationships become diluted or may
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Dick Heederik and Gert Doekes
have an unexpected shape because the different associations are superimposed. This
may be one of the reasons why several studies in the past have failed to find clear
exposure-symptoms relationships because of the complexities and pitfalls. Several
other studies explored relationships between exposure and symptoms in a straightforward way without finding a clear relationship. Exposure-symptom relationships
can only be studied in a meaningful way when the analysis is stratified for modifying
variables along the causal pathway, like sensitization and potentially atopy in the
case of HMW sensitizers.
The most evaluated exposure-response relationships in allergic respiratory
disease are exposure-sensitization and exposure-symptom relationships in crosssectional and some longitudinal studies. However, examples in which, for instance,
time to sensitization has been evaluated also exist [55]; these have shown that the
time to development of disease is also dependent on exposure intensity.
Special issues in exposure-response modeling
Some studies specifically explored the existence of exposure thresholds using
smoothing techniques [56–58]. There were no indications of an exposure threshold
or exposure level below which the sensitization risk was not increased. Others have
found levels below which sensitization did not seem to occur [40]. However, the difference between no or a few cases in the lowest exposed category and thus between
observing an exposure threshold or not seems small. The power of a study, the size
of the control group, the background prevalence of sensitization of the allergen, and
the way sensitization has been measured may be the major driving factors for the
estimated sensitization rate at the lowest exposure levels. The difference between
studies that do not find exposure thresholds and those that do are to some extent
relative and artificial, while the consequences for prevention and exposure standardsetting practices are obvious [59]. For some sensitizers health-based occupational
exposure limits (OELs) have been defined that specify the level of exposure to an
airborne substance, a threshold level below which it may reasonably be expected
that there is no risk of adverse health effects. When such a threshold does not exist,
an alternative approach would be to accept a low exposure, which carries a small
but predefined risk in developing allergic sensitization.
For several allergens, a flattening of the exposure-response relationship at higher
exposure levels has been reported [57, 58]. Some have argued that flattening off of
the exposure-response relationship may be associated with specific IgG and IgG4
responses at high exposure [60, 61]. Others observed the same phenomenon in
independent studies [62, 63]. However, this phenomenon was not observed in a
longitudinal study looking at IgG antibody response at baseline and incidence of
specific sensitization [64]. In one study it was found that the exposure-response
relationship for wheat exposure with specific sensitization differed from industry to
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Allergen and irritant exposure and exposure-response relationships
industry, possibly reflecting a differential selection bias (healthy worker effect) by
industry [57]. More studies are needed to understand the underlying explanations
for flattening of exposure-response relationships at high exposure levels.
Exposure-exposure interactions
Some environments with high levels of HMW allergens also appear to be associated with a strongly decreased risk of common atopy. Interactions seem to exist
between exposure to microbial agents like endotoxins and sensitization. Studies
among adults, some with occupational exposure data for microbial agents such
as endotoxin, have shown inverse relationships between endotoxin exposure and
atopic asthma [65], allergic sensitization [66], and hay fever [67, 68]. This suggests
complex and interacting associations between endotoxin and allergen exposures
in adult life. Similar complex interactions seem to exist with other exposures such
as disinfectants [12]. Evaluation of interactions as described above will become
more often the norm and not the exception. This will ask for studies with refined
exposure-assessment strategies and sufficient power to be able to distinguish the
effect of the different exposure variables on different phenotypes. An examples of
this development will be a new generation of gene-environment studies.
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Gene-environment interactions in occupational asthma
Francine Kauffmann 1,2, Francesc Castro-Giner 3,4,5, Lidwien A. M. Smit 1,2,
Rachel Nadif 1,2and Manolis Kogevinas 3,4,5,6
1
Inserm, U780 – Epidemiology and Biostatistics, Villejuif, France
Université Paris Sud, IFR69, Villejuif, France
3
Center for Research in Environmental Epidemiology (CREAL), Barcelona, Spain
4
Municipal Institute of Medical Research, Barcelona, Spain
5
CIBER Epidemiologia y Salud Publica (CIBERESP), Spain
6
Medical School, University of Crete, Heraklion, Greece
2
Abstract
This chapter reviews the existing knowledge regarding gene-environment interactions in occupational asthma. So far, studies have been conducted on relatively small samples, considering workers
exposed to specific hazards such as isocyanates or red cedar. HLA class II, genes in the antioxidant
defense, and more recently genes in the innate immunity pathway have been studied. As yet, few
interactions have been demonstrated; however, the development of large-scale genetic studies of
asthma will likely change the situation. Two types of approach can be developed based on testing hypotheses (candidate interactions) or in searching interactions with genes of yet-unknown
function that may be evidenced through genome-wide associations. Current challenges concern
the improvement of phenotypic and environmental characterization and setting up interdisciplinary research to understand the determinants of asthma. Building large international consortia on
asthma with data on occupational exposure is warranted.
Introduction
It is only recently that active search for both environmental and genetic determinants of common diseases, such as asthma has been undertaken [1, 2]. For classical occupational diseases such as coal workers’ pneumoconiosis, associations
of exposure with disease could be very strong. For such disease, exposure was a
necessary cause. On the other hand, not all those exposed develop the disease,
leading to the idea of individual susceptibility. However, there was some reluctance
to search genetic determinants because of concerns about the potential use of the
results. Moreover, the technology available for studying genetic factors was limited.
In one word, there was moderate interest for genetics by (traditional) epidemiologists. What were then called “genetic diseases” were in fact monogenic diseases and
without the deleterious variant, the disease did not exist. Finding the relevant gene
Occupational Asthma, edited by Torben Sigsgaard and Dick Heederik
© 2010 Birkhäuser / Springer Basel
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was done through familial studies on affected subjects by positional cloning. The
association of the identified deleterious variants with disease was usually very high.
Geneticists talked of penetrance to explain why not all individuals with the variant
get the disease. The heterogeneity of phenotypic expression was searched in relation to different variants of the gene, and possible gene-gene interactions, such as
modifier genes in cystic fibrosis. In other words, geneticists had little interest in the
environment at that time. It is now widely accepted that for complex diseases, such
as asthma, a more balanced view regarding the role of environmental and genetic
determinants is warranted.
Occupational asthma: A complex disease
Addressing the heterogeneity of asthma both at the phenotypic and etiological
level is a priority of research [3]. In that context, occupational asthma represents
one particular category of the disease among the persistent adult asthmas. Perhaps
more than in other complex diseases that occur only in adulthood, time is a crucial
element in asthma, a disease that can occur over the whole lifespan. Figure 1 shows
Figure 1.
Environment, genes, and time.
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Gene-environment interactions in occupational asthma
that time plays a role both through cohort effects and during the lifespan of individuals of the same cohort. For example, the prevalence of asthma has increased
two- or threefold during the last few decades, and occupational exposures in the
industrial and tertiary workforce have changed both qualitatively and quantitatively. During the life of an individual, it is critical to consider the window of
environmental exposure, i.e., when a specific exposure occurs, and the window of
genetic expression, i.e., when a given gene will play a role. Although time invariant,
genotypes do not play the same role over the lifespan. For example, some genes can
play a specific role in childhood growth or in the occurrence of adult onset asthma.
Early infancy appears to be a critical period for the development of allergy and
asthma. According to the so-called hygiene hypothesis, early contact with microbial
agents, for instance through contact with livestock may protect from allergy by
influencing immune system development. This hypothesis is consistent with immunological and epidemiological observations, but it is still lacking direct proof [4].
Adolescence with the occurrence of puberty, changing lifestyle and the beginning
of occupational exposures during training is a sensitive period. In occupational
asthma, interactions of genes with occupational exposures will occur in individuals
who already have a history regarding exposure to allergy and asthma risk factors
since birth. This is less the case for other work-related diseases, which do not share
as many features with non-occupational diseases. Interactions between various
genes, various environmental factors and between genes and environmental factors
act through specific pathways, and it is important to note that pathways are “ignorant” of the source of the exposures. In other words, the underlying mechanisms
explaining occupational asthma are general pathways that depend on numerous
non-occupational factors.
Whereas occupational factors are not always adequately considered in general
reviews regarding the etiology of asthma, occupational asthma may provide a model
to study asthma in general through a semi-experimental situation, inasmuch as the
start of exposure may be determined. Thus, understanding gene-environment interactions in the context of occupational asthma may provide clues to key pathways.
As detailed elsewhere in the book, occupational asthma is now considered the main
respiratory occupational disease in developed countries, and has been related to
exposure to many different substances (more than 300 have been described), with
a recent interest in irritants as a potential additional cause [5]. Most of the studies
have been conducted in occupational cohorts, a very efficient method for assessing exposure, but one that is subject to the healthy worker effect bias. The other
approach, by looking at the general population, is less subject to the healthy worker
effect, but faces the problem of assessing exposure. Methods have been developed
to assess exposure in these instances, such as asthma-specific job-exposure matrices, as described in other chapters. It is worth noting that there has not as yet been
a single published study on gene-environment interaction regarding occupational
asthma in general populations. Most studies with occupational characterization
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have not included data on genetic factors and most genetic studies on asthma have
not included data on occupational exposures.
The limited evidence regarding gene-environment studies suggests questioning
the pertinence of the issue: ‘Why do we need to study genetics in occupational asthma?’ ‘What will we gain from knowledge of genetics in the occupational setting?’ As
mentioned before, reluctance to conduct these studies may relate to anxiety regarding the potential use of findings on gene-environment interactions in the context of
occupational exposures. It should be stated clearly that such knowledge is needed to
improve the understanding of asthma and not to propose the selection of workers
based on genetic factors. It is the work that should be adapted to the most vulnerable. Legal protection regarding potential discrimination in relation to genetic tests
has been addressed both in Europe, and more recently in United States [6, 7]. While
remaining vigilant about the implications of research, occupational epidemiologists should do more studies on the combined effects of genes and environment to
improve the understanding of such complex diseases, to ultimately improve primary
and secondary prevention [8, 9].
This chapter reviews the existing knowledge and discusses strategies in the
changing context of genetic research. A glossary of genetic terms is given to help the
reader (Tab. 1). The candidate interactions strategy, based on a priori hypotheses
or knowledge is discussed. Finally, new challenges regarding the search of geneenvironment interactions for occupational asthma are discussed in the context of
genome-wide associations.
Table 1. Glossary of genetics terminology
Genetic term
Definition
Gene
The fundamental unit of heredity, made up of a sequence of
DNA that can be transcribed into messenger RNA and translated
into protein.
Chromosome
An organized gene-carrying structure composed primarily of
DNA and protein.
Genome
The whole set of DNA of an organism or a species.
Phenotype
Observable traits or characteristics of an individual.
Gene expression
The process by which inheritable information from a gene is
made into a functional gene product such as messenger RNA
and protein. Gene expression may be modulated as a response
to different developmental and environmental factors.
Common disease or
Complex disease
A disease or trait that is the result of multiple genetic and
environmental factors and the interaction between them.
Asthma is regarded as a complex disease.
208
Gene-environment interactions in occupational asthma
Monogenic disease or
Mendelian disease
Relatively rare disease caused by a modification in a single gene.
Penetrance
The probability that a genetic variant will be expressed on
a phenotypic level. For example, if the penetrance is 100%
(completely penetrant), then all individuals with the genetic
variant will express the phenotype.
Locus
A position on a chromosome of a gene or other chromosome
marker.
Allele
Alternative form of a genetic locus; a single allele for each locus
is inherited from each parent. The term allele is also used to
refer to DNA sequence variants.
Genotype
The genetic constitution of an organism; genotype can refer to
the entire genetic makeup, or the alleles at a specific locus.
Single Nucleotide
Polymorphism (SNP)
DNA sequence variation in a single nucleotide.
Functional SNP
SNP that influences a trait in a measurable way by altering the
activity of the protein or the gene expression.
Haplotype
Combination of genetic markers at different sites present on
neighboring, closely linked loci on the same chromosome.
Linkage disequilibrium
Describes the situation in which alleles occur together more
often than can be accounted for by chance.
Haplotype tagging
SNPs
A relatively small subset of representative SNPs that are needed
to uniquely identify a complete haplotype.
Positional cloning
Method to identify a gene for a specific disease or trait based on
its chromosomal location.
Candidate gene
A known gene which is suspected to be associated with the
disease or trait under study on the basis of the biological
function of its protein.
Genome-wide
Association Study
(GWAS)
Association study with a large set of genetic markers (up to
1 000 000) which captures a large proportion of common
variation in the human genome sequence. The objective is to
identify susceptibility genes associated with a disease or trait.
Multiple Comparisons
Refers to the problem that arises when multiple hypotheses are
tested, and some significant results are expected even if the null
hypothesis is true.
False Discovery Rate
(FDR) control
An approach to correct for multiple comparisons. FDR is the
expected ratio of erroneous rejections of null hypotheses to the
total number of rejected hypotheses.
209
Francine Kauffmann et al.
Literature review
Gene-environment interactions have been reported for only some of the agents
known to cause occupational asthma. In general, studies were based on small sample sizes and not always comparable phenotypes. Most studies investigated workers
exposed to isocyanates, which is to date the most evaluated occupational exposure
with at least 13 studies (Tab. 2). The genes evaluated reflect the two main pathogenetic mechanisms suggested for isocyanates: immunological and oxidative stress.
Interaction with the gene for human leukocyte antigen-II (HLAII) has been evaluated in 6 studies [10–15], leading to contradictory results but suggesting a critical
role of the HLAII DQB1 locus. Three studies evaluating polymorphisms in glutathione S-transferases (GSTs), which are enzymes involved in antioxidant defense,
have shown the importance of this mechanism in the protection against isocyanate
damage [16–18]. Other genes that have been associated with isocyanate-induced
asthma are involved in the metabolism of these compounds (N-acetyltransferases
NAT1 and NAT2), and in the inflammatory response [interleukin (IL)-4 receptor A
chain, IL-13, CD14, and neurokinin 2 receptor] [18–20]. More recently, in the first
genome-wide association study (GWAS) performed on occupational asthma, Kim
and co-workers [21] identified the catenin alpha 3, alpha-T catenin gene (CTNNA3)
as a new candidate for susceptibility to isocyanate-induced asthma.
Studies investigating other occupational exposures, including low-molecularweight sensitizers (acid anhydrides, platinum, plicatic acid), aluminum emissions,
and laboratory animal allergens are summarized in Table 3 and some illustrative
examples are presented in Tables 4 and 5. Most studies are underpowered, with
only two studies including at least 100 cases [22, 23]. In addition, there is almost
a complete lack of replication of results from these studies. Polymorphisms of the
HLA system have been associated with occupational asthma and/or sensitization
related to acid anhydrides [24–26], platinum [27], western red cedar wood [28],
and laboratory animal allergens [22, 29]. Two studies evaluating asthma among
aluminum smelter workers did not find significant associations for the genes
assessed [30, 31]. A study among young farmers (16–26 years) did not find associations between genes of the innate immunity pathway (CD14, TLR2, or TLR4)
and new-onset asthma [23]. However, a statistically significant effect of CD14/-260
and CD14/-651 on atopy was reported, and effects of both CD14 single nucleotide
polymorphisms (SNPs) appeared to be stronger among farmers who were born and
raised on a farm.
210
Type of study
Case-control
Case-control
Case-control
Case-control
Case-control
Case-control
Place (ref)
France and
Italy [12]
Italy [10]
USA [11]
Central
Europe [15]
Italy [14]
Italy [48]
Occupational
asthma
Occupational
asthma
Occupational
asthma
Total and
specific IgE
Occupational
asthma
Occupational
asthma
Occupational
asthma
Phenotype
HLAI A, B,
CTNF-A: A308G
HLAII-DQA1
HLAII-DQB1
HLAII-DRB1
HLAII-DRB1
HLAII-DQB1
HLAII-DQA1
HLAII-DRB1
HLAII-DQB1
HLAII-DQA1
HLAII-DQB1
HLAII-DQA1
HLAII-DQB1
HLAII-DPB1
HLAII-DR
Genes, genotype
TDI
TDI
MDI, TDI,
HDI
MDI, TDI,
HDI
TDI
TDI
Exposure
Table 2. Gene-environment interactions in asthma. Exposure to isocyanates.
HLA-I:
16/41
TNF-A:
142/45
67/27
32/23 and
90 nonexposed
10/15
30/12 and
126 nonexposed
28/16
Cases/
controls
Non-significant results
Frequency in cases vs controls
DQA1*0104: 24% vs 0%; p = 0.005
DQB1*0503: 21% vs 0%; p = 0.005
DQA1*0101: 10% vs 37%; p = 0.004
DQB1*0501: 13% vs 37%; p = 0.01
Non-significant results
Non-significant results
Frequency in cases vs controls
DQB1*0503: 30% vs 0%; pc = NS
DQB1*0501: 0% vs 25%; pc = 0.04, RR = 0.044
Frequency in cases vs non-exposed
DQB1*0503: 30% vs 13%; pc = 0.05, RR = 2.95
Risk alleles:
DQB1*0503 and DQB1*0201/0301
Protective alleles:
DQB1*0501, DQA1*0101, and DQA1*0101DQB1*0501-DR1 haplotype
Main results
Gene-environment interactions in occupational asthma
211
212
Type of study
Case-control
Case-control
Case-control
Case-control
Case-control
Place (ref)
Korea [13]
Finland [17]
Italy [16]
Finland [18]
Korea [20]
Table 2. (continued)
Occupational
asthma
BHR
IgE and IgG
VEGF
Occupational
asthma
Occupational
asthma
BHR
Occupational
asthma
IgE levels
Specific
bronchial
provocation
Occupational
asthma
Phenotype
NK2R: G7853A,
G11424A
NAT1 and NAT2:
slow acetylation
genotypes
GSTM1: null(–)
GSTM3: A, B
GSTP1: Val105/
Ile105
GSTT1: null(–)
GSTP1: Val105Ile
GSTM1: null(–)
GSTM3: A, B
GSTP1: Val105/
Ile105
GSTT1: null(–)
HLAI A, B, C
HLAII-DRB1
HLAII-DQB1
HLAII-DPB1
Genes, genotype
TDI
MDI, TDI,
HDI
TDI
MDI, HDI,
TDI
TDI
Exposure
59/93
109/73
92/39
109/73
55/47 and
95 nonexposed
Cases/
controls
Non-significant results for case-control study
7853 GG: increased VEGF levels in exposed;
p = 0.04
NAT1sa: OR = 2.54 (1.32–4.91) diisocyanate
NAT1sa: OR = 7.77 (1.18–52) TDI
NAT1sa+GSTM1null: OR = 4.20 (1.51–12)
NAT2sa+NAT1sa: OR = 3.12 (1.11–8.78)
NAT2sa+GSTM1null: OR = 4.53 (1.76–12)
GSTP1 Val/Val vs Ile/Ile: OR = 0.23(0.05–1.13)
Protective effect is greater at a longer duration
of exposure
GSTM1(–): OR = 1.89 (1.01–3.52) asthma,
OR = 0.18 (0.05–0.61) specific IgE
GSTM3 AA: OR = 3.75(1.26–11) late reaction
GSTP1Val/Val: OR = 5.46 (1.15–26) specific IgE
GSTM1(–) + GSTM3 AA: OR = 0.09 (0.01–0.73)
specific IgE, OR = 11.0 (2.19–55) late reaction
Frequency in cases vs controls
DRB1*15–DPB1*05: 11% vs 0%; p = 0.001
Frequency in cases vs non-exposed controls
DRB1*15–DPB1*05: 11% vs 2.5%; p = 0.003
Main results
Francine Kauffmann et al.
Case-control
Korea [21]
Occupational
asthma
Occupational
asthma
GWAS
IL4RA
IL13
CD14
TDI
MDI, TDI,
HDI
84/263
62/75
CTNNA3
rs10762058: OR = 1.68 (1.15–2.47)
rs7088181: OR = 1.80 (1.24–2.61)
rs4378283: OR=1.68 (1.15–2.47)
Significant results only for HDI:
IL4RA 50Ile/Ile: OR = 3.29 (1.33–8.14)
IL4RA 50Ile/Ile + IL13 110Arg/Arg: OR = 4.13
(1.35–13)
IL4RA 50Ile/Ile + CD14/–159CT: OR = 5.20
(1.82–15)
IL4RA 50Ile/Ile + IL-13 110Arg/Arg + CD14/–
159CT: OR = 6.40 (1.57–26)
Modified from [49].
BHR, bronchial hyperresponsiveness; CTNNA3, catenin alpha 3, alpha-T catenin; GST, glutathione S-transferase; GWAS, genome-wide association
study; HDI, hexamethylene diisocyanate; HLA, human leukocyte antigen; IL4RA, interleukin 4 receptor A chain; IL-13, interleukin 13; MDI, methylene
diisocyanate; NAT: N-acetyltransferase; NK2R, neurokinin 2 receptor; TDI, toluene diisocyanate; TNF-A, tumor necrosis factor alpha; VEGF, vascular
endothelial growth factor
Case-control
Canada [19]
Gene-environment interactions in occupational asthma
213
214
Type of
study
Casecontrol
Casecontrol
Casecontrol
Casecontrol
Casecontrol
Casecontrol
Case–
control
Place (ref)
Australia
[31]
USA [30]
UK [26]
Sweden
[25]
Sweden
[24]
South
Africa [27]
Canada
[28]
Occupational
asthma
Skin prick
test positive
to ACP
Sensitization
to acid
anhydride
Sensitization
to acid
anhydride
Sensitization
to trimellitic
anhydride
Occupational
asthma and
atopy
Occupational
asthma and
atopy
Phenotype
HLAII-DRB1
HLAII-DQB1
HLAII-DRB
HLAII-DPB
HLAII-DQA
HLAII-DQB
HLAII-DQB1
HLAII-DRB1
HLAI A, B, C
HLAII-DR
HLAII-DQ
HLA
ADRB2: Gly 16, Gln 27
High affinity-receptor of
IgE: Gly237Glu
TNF-A: A308G
Alpha 1-antitrypsin: M,
MM, MS, MZ
HLA
Ig: GM, KM allotypes
Genes, genotype
Western Red
Cedar (plicatic
acid)
Platinum
(Ammonium
hexachloroplatinate ACP)
Acid
anhydride
Acid
anhydride
Acid
anhydride
Aluminum
emissions
Aluminum
emissions
Exposure
56/63
44/57
52/73
53/47
30/28
13/39
33/127
Cases/
controls
DQB1*0603: OR = 2.9; p = 0.05
DQB1*0302: OR = 4.9; p = 0.02
DQB1*0501: OR = 0.3; p = 0.02
DRB1*0401-DQB1*0302: OR=10.3; p = 0.01
DRB1*0101-DQB1*0501: OR = 0.27; p = 0.04
D3: OR = 2.3 (1.0-5.6)
D6: OR = 0.4 (0.2-0.8)
Associations are stronger in lower exposed
subjects
DQ5: OR = 4.3 (1.7–11)
DR1: OR = 3.0 (1.2–7.3)
DQB1*0501: OR = 3.0 (1.2–7.4)
Frequency cases vs controls
A25: 0% vs 9%; p < 0.05
A32: 0% vs 13%; p < 0.01
DR3: OR = 6; p = 0.05
Non-significant results
Non-significant results
Main results
Table 3. Gene-environment interactions in asthma - Exposure to other occupational exposures.
Francine Kauffmann et al.
Casecontrol
Casecontrol
Nested
casecontrol
UK [22]
US [50]
Denmark
[23]
New-onset
asthma
Atopy: skin
prick test
Sensitization
to lab animal
allergens
Sensitization
to rat
lipocalin
Occupational
allergy
CD14: C-651T, C-260T,
C+1342A
TLR4: Asp299Gly,
Thr399Ile
TLR2: A-16934T,
Pro631His, Arg753Gln
TLR4: Asp299Gly,
Thr399Ile
HLAII-DQB1
HLAII-DRB1
HLAI A, B, C
HLAII-DR
Farm
environment,
endotoxin
Laboratory
animals,
endotoxin
Laboratory
rats (lipocalin
allergens)
Laboratory
animals
100/88
69/266
109/397
92/27
CD14/-260T: OR = 0.39(0.21-0.72) atopy
CD14/-651T: OR = 2.53(1.33-4.88) atopy
TLR4 299Gly: OR = 2.5 (1.5-5.5)
DR7: OR = 1.82 (1.12-2.97) sensitization
DR7: OR=2.96 (1.64-5.37) work-related chest
symptoms
DR7: OR = 3.81 (1.90-7.65) sensitization and
work-related chest symptoms
DR3: OR = 0.55 (0.31-0.97) sensitization
Frequency cases vs controls
B16: 0% vs 30%; p < 0.05
Modified from [49].
ADRB2, adrenergic receptor beta-2; HLA, human leukocyte antigen; TNF-A, tumor necrosis factor alpha; TLR, toll like receptor
Case–
control
Sweden
[29]
Gene-environment interactions in occupational asthma
215
Francine Kauffmann et al.
Table 4. Example 1– Distribution of DRB1 and DQB1 HLA class II alleles in occupational
asthma due to western red cedar [28].
Cases (56)
Controls (63)
OR [95%CI]
7.1
23.4
0.25 [0.08-0.79]
DQB1*0501
10.7
28.1
0.30 [0.11-0.82]
DQB1*0603
23.2
9.4
2.90 [1.01-8.17]
DQB1*0302
19.6
4.7
4.90 [1.28-18.6]
DRB1*0101
For the case control comparison, 37 other alleles were tested (17 with at least 5% in
controls).
Lowest p value = 0.0201 ; –log(p) = 1.7 [28].
Table 5. Example 2 – Occupational sensitization to rat lipocalin allergens and specific symptoms [22].
A
Sensitized
employees
(n = 109)
Non sensitized
employees
(n = 397)
UK blood
donors (603)
OR [95% CI]
DRB1*03
18.4
28.7
26.1
0.56 [0.33–0.95]
DRB1*07
39.5
28.5
26.7
1.64 [1.05–2.55]
B
Logistic regression (including age, sex,
exposure)
Sensitization
Sensitization and workrelated chest symptoms
DRB1*07
1.8 [1.1–3.0]
3.8 [1.9–7.7]
Atopy
4.8 [2.9–3.6]
5.0 [2.41–10.5]
Daily work in animal housing facility
3.8 [1.9–7.4]
5.5 [1.8–16.5]
Candidate interactions
In the ‘old’ days, that is in the 1970s, researchers were studying ad hoc genes
known at that time, such as ABO and HLA. Subsequently, there has been a move
to the study of ‘candidate genes’, i.e., genes for which what was known on their
physiological function appears relevant to explain the disease and a reasonable
hypothesis for the interaction. By qualification of a gene as a candidate, geneticists
216
Gene-environment interactions in occupational asthma
mean that the gene is studied because of a hypothesis, as opposed to genome-wide
approaches. This latter approach has been characterized by some as being agnostic
(etymologically: without knowledge) research [32]. By analogy, gene-environment
interactions defined by using previous knowledge can be named candidate interactions [33] (Tab. 6).
Knowledge may derive from preliminary findings regarding environment or
genes. In the context of occupational asthma, environment-gene interaction research
is primarily conducted using information on the potential mode of action of putative
or established occupational asthmagens. As shown by the literature review above,
interactions studied so far were based on a hypothesis-driven approach with genes
implicated on allergen recognition, second line antioxidant defense, and inflammatory response. Starting from the environment calls for pathways rather than single
genes, and until now it was more the excess rather than the lack of hypotheses
regarding potential genes that was a limitation. Hypotheses can be formulated based
on physiology, including animal models [34]. Because of the potential oxidative role
of numerous occupational asthmagens, it may be relevant to study all genes in the
antioxidant pathway, as well as all genes related to innate immunity when considering farming. However, very few studies have actually considered more than one gene
from the same pathway in a given study.
Numerous new candidate interactions could be studied such as interactions
of irritant exposures with genes from the transient receptor potential (TRP) family [35]. There is increasing concern that exposures to irritants less extreme than
those observed in reactive airway syndrome occurring after inhalation accidents
could lead to asthma. Thus, genes from the TRP family, which includes the channel receptor for capsaicin and in particular TRPV1 (also named vanilloid receptor,
VR1) are good candidates. Capsaicin is a strong irritant, inducing a cough, and is
an occupational hazard in chili pepper workers [36]. As women usually exhibit a
more nocturnal cough, and cough at a lower level of exposure to capsaicin, it could
be hypothesized that, in such an example, it is not asthma in general that should
be studied but the subphenotype in which nocturnal cough is present and taking
gender into account.
Studying all genes in the genome-wide association era?
Since 2007, numerous genome-wide associations have led to discoveries of new genes
for a variety of disorders. A current format is to genotype for 100 000–1 000 000
SNPs per individual in series of at least 1000 cases and 1000 controls. In the Wellcome trust case-control study for example, 14 000 cases of seven common diseases
(not asthma) were studied versus 3000 shared controls. It allows most established
loci for these diseases to be replicated – an important proof of concept of the method – and to determine new pathways [37].
217
218
(Known) pathway
approach
Precise hypothesis
I - Candidate interaction
G known s E known
+ Good power
+ Fits with GWAS strategy
– Loss of G s E evidence
Most G s E interactions
are weak
Marginal effects first G
asthma and E asthma
Studies on exposures without
considering genetics Studies on
genotypes without considering
environment
+ Data will be available, low cost
+ Easy statistically
– Lack of biological plausibility if function
of both G and E are known but pertain
to different pathways
– Possibility of chance finding
Hypothesis driven:
additive effect
expected, test for
synergy, possibly new
pathway
E known for asthma s G
known for asthma
TDI s IL-13
Plicatic acid s ADAM33
– Need for replication in another
population.
– Possibly lack of biological plausibility
Need for further experimental studies
to determine the underlying biological
process
+ Relevant in general population studies
HLA, GST with any asthmagen
Possibly find new
pathway
+ Biological plausibility and easy
interpretation More robust result
– Subject to a priori knowledge
Comments
HLA with TDI
Examples
II - No candidate
interaction
G known s E not very
precise
Rationale
Strategy
Table 6. Gene-environment interactions – From the simplest to the most complex strategy of analysis in the GWAS era.
Francine Kauffmann et al.
Relevance for
occupational
exposure (adult onset,
immunological or non
immunological, etc.)
No a priori hypothesis
of any sort
Subphenotypes first
(independent of exposure)
All G with all E
Consider hundreds of
occupational asthmagens or
all putative environmental
determinants of asthma with
all genes
GWAS on IgE-dependent
occupational asthma, studies
on asthma with irritant cough
Search of interactions of all
genes with TDI (done by [21])
Huge problem of multiple comparison,
E not well measured
+ Increase strength of association, address
phenotypic heterogeneity
– Small samples – Need of collaboration
+ Not loosing the evidence of interaction
– Dimensional problem not solved
– Exposures usually basic, or sample size
problem
G, gene; E, environment
+ Advantage of the strategy
– Limitation of the strategy
ADAM33, a disintegrin and metalloprotease 33; GST, glutathione S-transferase; GWAS, genome-wide association study; HLA, human
leukocyte antigen; IL-13, interleukin 13; TDI, toluene diisocyanate
Focus on the question
of interaction
G s E for all genes
Gene-environment interactions in occupational asthma
219
Francine Kauffmann et al.
A genome-wide association study (GWAS) for asthma was performed in the
Gabriel European consortium among children [38]. Potential associations of asthma (yes/no, simply defined) with approximately 300 000 SNPs across the genome
were searched. The analysis took into account multiple comparisons using the false
discovery rate statistic. The results evidenced the role of ORMDL3 on chromosome
17q21, with the first replication sample from the International Study of Asthma
and Allergies in Childhood (ISAAC) [38]. An important aspect to consider is that,
similar to GWAS in other diseases, the effect size was small, with an odds ratio for
ORMDL3 of only 1.5. Hence, the new genes that are currently being discovered
may correspond to weak associations with the phenotype under study. Analyses
conducted in the French epidemiological study on the genetics and environment
of asthma (EGEA) have confirmed the association of 17q21 variants with asthma
and showed that, in this population including both children and adults, the association was restricted to early-onset asthma [39], and therefore not a candidate for
occupational asthma. In the future, industrial samples will also be included in such
GWAS, and it is anticipated that genes common to asthma in general and specific
to the exposures will be found. In addition, it would be interesting to study genes
in relation to intermediate phenotypes or subphenotypes in contrasted groups of
exposure. However, very large numbers are needed to allow interactions with specific exposures, and the necessary pooling and replication raise questions regarding
population ascertainment, comparability of phenotypes, the heterogeneity of exposure, and geographical/ethnic differences regarding allele frequencies.
Although starting from hypotheses related to occupational asthmagens was the
primary rationale in the past, the situation may evolve with the evaluation of results
from GWAS. An example of this is the search of exposure by gene interactions that
is using previous knowledge on exposure to choose the genes to study. Using the
increasing knowledge on new genes (e.g., the association with age at onset or a precise knowledge of its function) should help to focus the search of genes involved in
occupational hazard exposure interactions. To discover gene-environment interactions, strategies without hypotheses are also possible, but these face major problems
of sample size. Although too underpowered to be really conclusive, the first GWAS
conducted for toluene diisocyanate (TDI)-induced asthma suggested the involvement of a gene not previously hypothesized to play a role (CTNNA3) [21]. However,
as there is no specific hypothesis for interaction with TDI, the primary replication to
be performed may be with asthma in general, and not specifically with TDI-induced
occupational asthma. On the other hand, it could point to a gene specific for the
subphenotype of TDI-induced occupational asthma. In that case, replication with
appropriate confidence would need a much larger sample size.
If GWAS show genes with an already known function, the strategy that should
be followed is that of candidate interactions, i.e., using the existing knowledge.
In the case of discoveries of genes with unknown function, other strategies may
be implemented. Table 6 illustrates that numerous strategies are possible to assess
220
Gene-environment interactions in occupational asthma
environment by gene interactions from the most hypothesis-driven to the most
agnostic ones. Some are common; some may seem unfeasible for now. Unless the
interaction is hypothesized to be massive, it can also be argued that it is more appropriate to look first at marginal effects instead of looking at every environment in
potential interaction with every genetic marker.
Challenges on the genetic, phenotypic, and environmental aspects
Multiple comparisons
Multiple comparisons are not a new issue. In the example presented in Table 4, the
odds ratio of 4.9 for DQB1*302 in relation to exposure to red cedar asthma has to
be put in the context of the study in which 37 different alleles were tested [28]. The
association is not statistically significant if the number of comparisons is taken into
account. To illustrate the issue of multiple comparisons, a p value of 5 × 10–6, i.e.,
–log(p) around 6, is needed in the context of GWAS done with 300 000 SNPs, such
as in Gabriel [38] based on a 5% false discovery rate, i.e., a classical p value for a
simple comparison. If one considers now an MHC-wide test for only 1270 SNPs,
–log(p) needs to be around 4.4, based on Bonferroni correction [40]. However, if
the significance of only 183 HLA class II SNPs were examined in that array, –log
(p) would decrease to 3.6 [41]. Finally, if looking only at 3 SNPs in the CTNNA3
gene for example, the requested p value for significance will remain in the area of
classical studies.
Extracting the relevant information from large tables, such as those of
GWAS is difficult
Informatic tools are currently being developed to reduce extremely large data sets
to study either gene-gene or gene-environment interactions [42, 43]. Other methods, hypothesis-driven, can be considered, e.g., Bayesian combination of candidate
genes, using the accumulation of knowledge on the first genes to go further either
by studying genes in a given pathway (such as a gene controlling the production
of a protein and the gene controlling the receptor of that protein) or not (such as
by taking into consideration prior evidence – possibly belief – regarding the role of
genetic determinants). Relaxing the level of significance when studying associations
with selected exposures may be considered, i.e., balancing the cost benefit of lack of
power and false discovery. Note that in searching for an association with genes, we
are in a situation different from that in a clinical trial: a wrong conclusion will not
kill any patient to whom the inappropriate treatment is given, we just loose time by
pursuing on wrong hypotheses that will not be replicated.
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Francine Kauffmann et al.
A difficulty in the current period when studying candidate genes is the mode
of choice of SNPs in large series of genotyping. If they are chosen based only on
known function, the possibility of discovering new genes is limited. If they are
chosen based only on haplotype blocks, the possibility of testing functional SNPs
is limited. Furthermore, it is current practice not to genotype low frequency alleles
due to power issues, whereas these may be the functional ones. It is well possible
that the common disease-common variant model will not be sufficient to understand
complex diseases such as asthma, and that rare alleles of major effect may explain
the observed heterogeneity [44]. To address this question, the relevance of sequencing DNA in the context of specific studies is currently discussed. Such a strategy
puts emphasis on improving the genetic characterization. Clearly, the appropriate
balance in the improvement of phenotypic, environmental and genetic characterization is a challenge.
Looking at the appropriate phenotype is a challenge
What needs to be done after finding some new genes associated with asthma? Since
GWAS in asthma and other diseases tend to evaluate a single phenotype that can be
easily measured in different studies, the next step should probably be to look back
at that same question but with improved phenotyping. One proposal is that the
second step should be to consider a few of the SNPs (e.g., less than 10) evidenced
for the “new” gene and to search associations with numerous phenotypes, i.e., the
phenome. The order of magnitude may then be of the order of 1000 comparisons,
representing a problem much easier to handle statistically than comparisons on
300 000 SNPs. This analysis on subphenotypes may suggest clues regarding the function of the gene. Subphenotypes may relate to age of onset, allergic characteristics,
but more generally to a variety of subphenotypes. Asthma starting in adulthood is
a pertinent subphenotype regarding the role of occupational determinants, whereas
the subphenotype of asthma active in adulthood is pertinent regarding the role of
occupational factors implicated in work-aggravated asthma as well as (new-onset)
occupational asthma. Obviously other means to understand gene function exist
(including expression studies, animal models, etc.). The difficulty with the above
phenome strategy will come from the absolute need for replication. Therefore, either
such studies should be planned when relatively similar phenotypic characterization
exists in various data sets, or when it is easy to improve phenotypic characterization
very quickly. Large consortia with standardized detailed phenotyping are necessary
and such consortia are currently being built.
There is a need of refining phenotypic characterization in complex diseases such
as asthma. Improved phenotyping concerns clinical phenotypes with the development of more international standards. Further, ordinal or quantitative scores instead
of dichotomous (diagnosis) definitions seem of great interest. That particular aspect
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Gene-environment interactions in occupational asthma
is similar to issues regarding classification of occupational exposures using probability and intensity in job exposure matrices, instead of yes/no criteria. Another
aspect is to study intermediate phenotypes, sometimes called endophenotypes. This
may vary from total IgE, to gene expression data obtained from RNA, or to proteomics, which is likely to represent a source of major improvement in phenotypic
characterization in the next few years. Such data are often quantitative. However, it
is not always obvious whether they are true intermediate phenotypes (i.e., between
the gene and the disease) or only associated traits (i.e., possibly a consequence of the
disease). In fact, the pertinent item is not an SNP, or a gene, but rather biological
pathways. Improving phenotypic characterization towards more biological-oriented
approaches should be an efficient means to decrease the multiple comparison issue,
using for example Bayesian approaches.
After that step, potential interactions with the environment may remain totally
obscure or not. A genetic variant only associated with childhood onset asthma
will not be a good candidate for interaction with occupational exposure; a genetic
variant only associated with asthma with nocturnal cough might be candidate for
an interaction with exposure to irritants, etc. If a candidate interaction approach
cannot be taken after step 2, a step 3 approach could be implemented that searches
all the potential interactions of the few SNPs (less than 5) with very few subphenotypes (less than 5), considering now all the environmental characteristics (termed
the envirome or exposome). Here again, the number of variables will remain much
lower than for the genetic variants, probably the same order of magnitude as for
the phenome phase, i.e., 1000 variables. Again, without a replication sample, such
a strategy cannot be set up.
Improving environmental characterization is a challenge
There is a general need for standardization in an interdisciplinary context. Measurement bias is known for genotypes by geneticists, for phenotypes by epidemiologists
and clinicians, for exposures by environmental epidemiologists and toxicologists.
Interdisciplinary teams should address those comprehensively [45]. The insufficiency of the precision regarding exposure is a key aspect, and as plied by Wild [46],
it is necessary to complement the genome by an “exposome” with good precision.
Beyond the disease phenotype, new “omics” such as proteomics and metabolomics
should improve the assessment of exposure.
Conclusion
Research on gene-environment interactions in occupational asthma has been limited and findings have not been adequately replicated. Research regarding genetics
223
Francine Kauffmann et al.
in common diseases is rapidly evolving, and it is likely that in the next few years
several new genes, possibly of yet-unknown function, will be suggested as potential
determinants of asthma following GWAS. These genes with relatively common
variants will probably have relatively weak effects but some of these genes may be
relevant to study further and and help us understand the development and evolution of occupational asthma. Other studies will be needed to find potentially new
genes with rare variants but larger effects, which may also explain the occurrence
of occupational asthma. Based on hypotheses (candidate interactions) or directly
using “omics” approaches on interactions by strategies not yet determined, new
studies may help to find other genetic variants that interact with occupational
asthmagens. The study of gene-environment interactions focused on occupational
asthmagens will increase our understanding of the disease in general. It is important
to remind that association does not mean prediction [47], and that risks need to be
very high to predict disease in a given individual. Identification of gene-environment
interactions, at least in the short term, will probably not help improve primary and
secondary prevention of asthma or the management of the disease. Improvement
of the evaluation of environmental/occupational exposures is needed for studies,
irrespective of whether they consider or not the role of potential interactions with
genetic determinants. Gene-environment interaction studies should not slow the
study focused on the search for the associations of occupational exposures with
asthma and prevention of such workplace exposures.
Acknowledgments
This review was supported by the Ga2len project (Global Allergy and Asthma
European Network) EU-FOOD-CT-2004-506378 (working packages 2.9 and 2.4).
F Castro-Giner was partly supported by a grant from the MaratoTV3, Catalonia,
Spain. LAM Smit was supported by an European Academy of Allergy and Clinical
Immunology (EAACI) – Ga2len exchange fellowship.
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Asthma in apprentice workers
The birth cohort parallel: Using apprentices as a powerful
cohort design for studying occupational asthma
Denyse Gautrin and Jean-Luc Malo
Axe de recherche en santé respiratoire, Hôpital du Sacré-Coeur de Montréal, 5400 Gouin
Blvd West, Montreal, Canada
Abstract
This chapter presents a review of longitudinal studies of apprentices in trades and professions
entailing substantial risks for the development of occupational asthma (OA). Prospective studies
of OA enable the assessment of host characteristics before apprentices/workers enter a particular
workforce, thus before being exposed to a suspected etiological agent, as well as the early detection
of sensitization to a specific work-related antigen and the evaluation of bronchial responsiveness
before onset of symptoms of asthma. Since 1973, several cohort studies have been conducted in
Europe and Canada among apprentices exposed to high- and low-molecular-weight agents. The
investigated outcomes were, apart from OA, work-aggravated asthma, bronchial hyperresponsiveness, work-related symptoms and specific sensitization. The rate of onset of the relevant outcomes
was high even after 1 year of training; the implications for setting timing of surveillance programs
would be to screen for sensitization and symptoms in the first 2–3 years of apprenticeship. Several
host factors assessed at baseline were identified as risk factors for the incidence of work-related
outcomes. However, more investigations are needed to explore the extent to which the risk of
work-related allergy and asthma increases with exposure characteristics during apprenticeship.
Directions for research in the existing cohorts and in future ones are suggested.
Introduction
This chapter reviews studies of apprentices in trades and professions entailing
substantial risks for the development of occupational asthma (OA). Most of the
apprentice studies were designed with the objective of gaining a better understanding of the natural history of work-related asthma and identifying the host risk factors; a few of these aimed at a better characterization of the causal exposure.
Occupational Asthma, edited by Torben Sigsgaard and Dick Heederik
© 2010 Birkhäuser / Springer Basel
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Denyse Gautrin and Jean-Luc Malo
Concept of the model of occupational asthma
It was suggested by Becklake [1] that studying OA could provide useful information
on the relationship between some environmental risk factors and the development
of asthma since, with OA, etiological agents can be identified and measured. In the
early nineties Malo and Chan-Yeung [2–4] proposed that the natural history of OA
be used as an ‘experimental’ model in studying the development of asthma. This
model enables the assessment of host characteristics before workers enter a particular workforce, thus before being exposed to a suspected etiological agent, as well as
the early detection of sensitization to a specific work-related antigen [in the case of
exposure to a high-molecular-weight (HMW) agent] and the evaluation of bronchial
responsiveness before any possible onset of symptoms of asthma. Furthermore, the
prognosis for asthmatics as well as the reversal of bronchial hyperresponsiveness
(BHR) can be studied after workers are removed from exposure (Fig. 1).
To document the natural history of work-related asthma, the most suitable
populations to study would be newly hired individuals, apprentices, or students
in workplaces or vocational schools where there are high risk exposures. Since
these groups are mostly naïve in terms of contact with work-specific allergens, the
Figure 1.
Natural history of occupational asthma; stages of the natural history; factors influencing the
onset and prognosis.
230
Asthma in apprentice workers
approach of choice would be to set up epidemiological prospective cohorts of these
specific populations.
In prospective studies, subjects are selected on the basis that they are exposed to
the factor under investigation, but in whom the disease has not yet manifested itself.
The investigator must conduct a follow-up of the cohort members for an appropriate period to ascertain the disease’s status; for example, the outcome(s) of interest.
The most appropriate approach is to assemble the cohort prior to exposure, or upon
their initial employment, thus allowing for the comparisons to be made internally;
for example, between cases and non-cases to determine the effect of exposure and
other potential determinants [5]. When the cause of the disease is known, prospective cohort studies may be undertaken to meticulously assess exposure to quantify
exposure-response relationships. There are examples of recent longitudinal studies
in workers exposed to laboratory animals or baker’s allergens to explore exposureresponse relationships with the long-term objective of reducing the incidence of allergic sensitization and respiratory symptoms through a better control of exposure [6].
From a different perspective, the natural history of asthma has been assessed in
birth cohorts such as the well known Dunedin (New Zealand) study, initiated in
1972–1973, to study the development of a broad spectrum of diseases [7]. There
have been European birth cohorts on asthma, allergic rhinitis and atopic diseases
that were initiated in the 1990s in eight countries [8].
However, birth cohorts and apprentice cohorts on asthma present some similarities. They are both designed to assess periodically selected outcome measures for
atopy, allergic sensitization to specific agents, rhinitis (allergic or not) and asthma.
The cohort members are enrolled at birth or upon starting their apprenticeship
while they are still naïve with respect to exposure(s) that is specific to their new
environment; in particular to allergens. At that time point, the so-called baseline
host characteristics and other potential risk factors, e.g., smoking (maternal/personal), are documented. Birth cohorts are usually assembled to represent the general
population in a determined geographic area over 1 or more calendar years; whereas
apprentice cohorts are restricted to individuals at risk of developing work-related
asthma and related conditions, the latter possibly being more limited in terms of
size since the expected rate of outcomes is greater than in birth cohorts. A major
difference arises in the identification of the causal agent(s) with one or several ubiquitous allergens of various types (pets, pollens, mites, molds, etc.) in birth cohorts,
as opposed to a limited number of agents specific to the environment of a particular
training program such as, flour and A-amylase in baking apprenticeship.
The application of the model of occupational asthma
The profile of individuals prior to being exposed at work/during apprenticeship can
be assessed through a number of tools. Questionnaires, in particular those devel-
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Denyse Gautrin and Jean-Luc Malo
oped for the European Respiratory Health Survey [9], are administered to determine
the history of allergic diseases, symptoms suggestive of asthma, allergic symptoms,
other respiratory symptoms, as well as smoking habits and exposure to pets. Other
standardized questionnaires have just started being used in prospective studies of
OA to assess mental health, in particular depression and anxiety status. Skin-prick
tests [10] and serological tests are used to determine the immunological status to
common allergens and also to the specific work-related allergen(s) under investigation. Finally, methacholine/histamine/adenosine-5’-monophosphate challenge tests
are used to assess bronchial responsiveness [11–13]. All these tests can be and
have been administered within the confines of the teaching institutions by trained
research nurses and medical technologists. A modified protocol for bronchial challenge tests was developed and the safety of the test has been confirmed [14].
The design of these studies enables the prospective assessment of exposure to the
agent(s) under investigation as well as of the potential confounding factors such as
exposure to other contaminants in the workplace (e.g., to irritant products), viral
infections, and continuous or discontinuous smoking.
The repeated assessments of health outcomes from the beginning of the apprenticeship onwards provide the opportunity of observing the trend in the incidence of
relevant signs and symptoms of occupational allergy in the population studied as
well as following the sequence of individual outcomes over time.
A pitfall in all prospective studies is the loss to follow-up and the effects this
may have on the interpretation of the results. In occupational studies, the ‘healthy
worker’ effect is known to occur when workers who experienced work-related
health conditions have left the workplace. In the proposed apprentice model, both
the assessment of the baseline host characteristics and the on-going evaluations of
new sensitizations and work-related symptoms provide information to characterize
those who quit the apprenticeship and assess the likelihood of selection biases [15].
The selected study population can theoretically be workers newly hired in an industry or apprentices starting a training program in a vocational school; indeed both
populations are recruited when they have no earlier exposure to the agent. However,
it is more efficient to select a cohort of apprentices since groups of individuals start
exposure at the same point in time (study year) rather than spread over time such
as for new workers.
A possible limitation worth considering for some apprentices studies (e.g., those
involving laboratory animal workers and agricultural workers), is that they may
have had exposure to the relevant allergens earlier. Lab animal workers sometimes
had a past in agriculture like farmer apprentices and so they are not truly naïve
with regard to the exposure. However, interestingly, in a study of 769 apprentices
in four different sectors: lab animal technology, veterinary medicine, pastry-making
and dental hygiene technology, the prevalence of allergic sensitization to laboratory
animals at entry into the apprenticeship was the same (6.8–7.4%) in each group
[11].
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Asthma in apprentice workers
Studied apprentice populations
Cohorts of apprentices in trades that entail exposures to various respiratory sensitizers and irritants, who are thus at risk of developing OA, have been studied in several
countries. Published by Herxheimer in 1973 [16], the first long-term examination
was completed in Germany in a large group of 880 apprentice bakers, a small
number (n = 37) of them were followed for 5 years. The percentage of skin sensitization increased gradually over the years until the third year when it reached 19%
(54/290); at that time, complaints suggestive of an allergic disease occurred in 7% of
apprentices, half of them were skin positive to either flour or other allergens. Since
then, a number of prospective studies in trainee bakers and pastry makers have been
conducted in Sweden [17], Italy [18], The Netherlands [13], Canada [19], Poland
[12] and Denmark [20]; details of most of these studies, and main findings are summarized in Table 1. In Canada, inception cohort studies of apprentices exposed to
different types of HMW agents derived from laboratory animals and latex were
conducted among animal-health technicians [11, 21, 22] and dental hygienists [23].
Other populations of apprentices followed prospectively were mainly exposed to
low-molecular-weight (LMW) agents; they included a Canadian cohort of apprentice
machinists exposed to metalworking fluids [24], another Canadian cohort of apprentice welders exposed to welding fumes [25], a group of hairdressing apprentices in
France [26], and apprentice car-painters in Canada [27]. Furthermore, an Italian
group of investigators conducted a longitudinal study of apprentices from different
trades exposed to various airway occupational sensitizers and irritants [28].
Investigated outcomes (events)
The central and long-term outcomes considered in the published cohorts of
apprentices are OA and more recently its variants such as work-aggravated asthma
[20]. OA was only confirmed objectively using specific inhalation challenge tests
in the Polish cohort study [12]. The nearest outcome to OA was a combination
of: (1) a significant increase in bronchial responsiveness defined as a 3.2-fold (or
2-fold) decrease in PC20 in a methacholine challenge test; and (2) sensitization to
apprenticeship-specific allergens when the causal agent is an HMW allergen [22]
or incident work-related asthma-like symptoms in the case of LMW agents when
an immunological mechanism has not been confirmed [24, 25]; the term ‘probable
OA’ has been used for these groupings of outcomes. Several other endpoints related
to OA or considered as intermediate conditions have been evaluated. These include
occupational rhinitis, confirmed through nasal specific inhalation tests as performed
in symptomatic persons within the Polish cohort of apprentice bakers [12], or
defined as the incidence of both specific sensitization to an occupational allergen
and work-related symptoms of rhinitis [19].
233
234
No.
recruited;
no.
followed
880; 290,
(37)
125
230; 188
Apprentice
population,
agent(s)
Bakers, flour
Bakers, flour,
A-amylase
Pastry
makers, flour
1.4
2.5
3, (5)
Duration
(years)
4.2 per
100 PY
13.1 per
100 PY
1.3 per
100 PY
Work-related
symptoms of RC
Skin sensitization to
flour + work-related
RC symptoms
9%
Work-related
respiratory symptoms
Skin sensitization to
flour
10.1%
19%
Incidence
Skin sensitization to
occupational allergens
Skin sensitization to
flour
Outcomes of interest
–
Skin sensitization
to wheat flour;
persistent rhinitis
Hay fever; skin
reactivity to grasspollen; father with
asthma
History of allergic
disease
ND
Skin sensitization
to pollen
Baseline host
–
ND
ND
Skin sensitization
to wheat,
flour/Aamylase
ND
Skin sensitization to
pollen
During
follow-up
Factors
–
ND
ns
ND
ND
ND
Exposure
Gautrin,
2002,
Canada
De Zotti,
2000, Italy
Herxheimer,
1973,
Germany
First author,
year, country
[29]
[18]
[16]
Ref.
Table 1. Summary from prospective cohort studies of apprentices in high-risk industrial sectors with exposure to agents causing occupational asthma.
Denyse Gautrin and Jean-Luc Malo
461; 287
187; 114
417; 387
Bakers, flour
Bakers, flour,
A-amylase,
moulds, mites
Animal-health
technicians,
laboratory
animals
1.6–3.6
2
2
Skin sensitization
to pets; BR
2.7 per
100 PY
24%
9.6%
Skin sensitization to
lab animals + Increase
in BR (3.2-fold
decrease in PC20)
Work-related RC
symptoms
Skin sensitization to
lab animals + workrelated RC symptoms
Skin sensitization
to cats; BR
Skin sensitization
to grass pollen;
rhinorrhea on
contact with dust;
chest tightness;
cough
Atopy; respiratory
symptoms in the
pollen season
8.9 per
100 PY
6.1%
Occupational
sensitization
Atopy; female
Atopy; skin sensitization to occupational allergens
Atopy
Atopy; history of
skin symptoms
Skin sensitization to
lab animals
10.0 per
100 PY
8.7%
Occupational
asthma‡/chronic
cough
Asthma-like
symptoms
12.5%
Occupational rhinitis†
22.1 per
100 PY
8.6%
Work-related chest
symptoms
Work-related rhinitis
8.2%
Hypersensitivity to
occupational allergens
ND
ND
ND
ND
BHR
ND
ND
ND
ns
ns
Duration of
exposure
Rodier, 2003,
Canada
Gautrin,
2001,
Canada
Gautrin,
2000,
Canada
Skjold, 2008,
Denmark
Walusiak,
2004, Poland
[19]
[22]
[21]
[20]
[12]
Asthma in apprentice workers
235
236
No.
recruited;
no.
followed
122; 110
297; 191
(referents:
248; 189)
95; 82
(referents:
202; 157)
286; 194
Apprentice
population,
agent(s)
Dental
hygienists,
latex
Hairdressers,
sensitizing
materials
with irritant
exposure
Machinists,
metalworking
fluids (MWF)
Welders,
welding
fumes
Table 1. (continued)
1.25–1.5
2
2–3
1.5–2.5
Duration
(years)
11.9%
3.1%
Increase in BR (3.2fold decrease in PC20)
Increase in BR +
work-related chest
symptoms
BHR + asthma-like
symptoms
7% vs
2%
Mean
(SD) –2.5
(8.4) vs 0
(7.4)
Change in FEV1 (%
predicted)
Increase in BR (2-fold
decrease in PC20)
13% vs 7%
10.0% vs
11.5%
ND
ns
Atopy
ND
1.8 per
100 PY
Skin sensitization to
latex + increase in BR
(3.2-fold decrease in
PC20)
Respiratory symptoms
(wheezing)
Atopy; history of
asthma
Baseline host
2.5 per
100 PY
Incidence
Skin sensitization to
latex
Outcomes of interest
ND
ND
ND
ND
ND
During
follow-up
Factors
ND
Duration of
exposure
to synthetic
MWF
No specific
hairdressing
activity; no
working
conditions
ND
ND
ND
Exposure
El-Zein,
2003,
Canada
Kennedy,
1999,
Canada
Iwatsubo,
2003, France
Archambault,
2001,
Canada
First author,
year, country
[25]
[24]
[26]
[23]
Ref.
Denyse Gautrin and Jean-Luc Malo
385; 298
Car-painters,
diisocyanates
(HDI)
1.5
1.25–1.5
6.4%
4.4%
Work-related chest
symptoms
13.8%
Work-related nasal
symptoms
HDI-specific IgE and
IgG
Welding-related chest
symptoms
Inversely related
to IgE levels;
physiciandiagnosed asthma;
BHR
Inversely related to
IgG4 levels
none
Possible
MFF
Duration of
exposure
during
training
Dragos,
2008,
Canada
El-Zein,
2005,
Canada
[27]
[37]
‡
: Based on questionnaire data and positive reaction to a specific inhalation challenge (SIC);
: work-related chest symptoms and positive SIC;
MWF: metalworking fluids; PC20: provocative concentration of nonspecific agent causing a 20% decrease in FEV1; FEV1: forced expiratory volume
in 1 second; BHR: bronchial hyperresponsiveness; BR: bronchial responsiveness; RC: rhinoconjunctivitis; PY: person-years; ND: not assessed; ns: non
significant; MFF: metal fume fever.
†
286; 232
Welders,
welding
fumes
Asthma in apprentice workers
237
Denyse Gautrin and Jean-Luc Malo
The aforementioned outcomes – sensitization to allergens specific to the apprenticeship (specific IgE or skin-prick test reactivity), work-related nasal, ocular and
chest symptoms, and increase in bronchial reactivity – have also been considered
separately to determine their incidence and/or determinants (see Tab. 1).
Major findings
Incidence
OA can develop during a 2-year apprenticeship in a bakery. In the Polish cohort
the proportion of cases was 8.7% after 2 years of training, with symptoms of
wheezing occurring after a mean (± SD) latency period of 15.1 ± 5.1 months [12].
In the Canadian cohort of apprentice bakers, no cases of probable OA were
observed. However, incident cases of probable OA were detected in the cohort of
apprentices in animal health with a rate of 2.7 per 100 person-years (PY) [22].
Among apprentice machinists exposed to metalworking fluids, 7% developed new
bronchial responsiveness with asthma-like symptoms [24], while the incidence was
3.1% in apprentice welders [25]; both these Canadian cohorts were followed over
2 years.
Occupational rhinitis was also detected and confirmed in 12.5% of Polish
apprentice bakers, a slightly higher proportion than for OA [12]; the incidence of
probable occupational rhinitis among Canadian pastry-making apprentices was low
(1.3 per 100 PY) compared to that of work-related symptoms of rhinoconjunctivitis
with no specific sensitization to flour (13.1 per 100 PY) [29].
Specific (skin) sensitization to the relevant work-related allergen(s) was assessed
in all cohorts of apprentices exposed to HMW agents. The findings are reported
in Table 1 and suggest that the incidence is greater among individuals exposed
to laboratory animals than to baker’s allergens. The proportions of apprentices
showing a twofold dose decrease or more in PC20 was 13% and 11.9% in apprentice machinists and welders, respectively. Interestingly, although an increase in
bronchial responsiveness may be believed to be nonspecific, the increase was significantly greater in machinists than in apprentices in various other construction
trades [24].
A proportion of individuals without prior exposure to an occupational allergen
may be sensitized to such allergens before enrolling into a vocational program [11,
12]. Sensitization to flour or A-amylase present when starting training in pastrymaking or bakery is a risk factor for the future development of work-related respiratory symptoms [12, 18, 29].
238
Asthma in apprentice workers
Time course of ‘events’ (stages)
The time course of relevant outcomes during an apprenticeship was described
through repeated assessments [12, 30]. The rate of new work-related rhinoconjunctivitis symptoms and sensitization to training-specific allergens assessed yearly
among apprentice animal-health technicians was greater than 10% after 1 year of
training and remained high after 2 and 3 years; the rate of new work-related chest
symptoms was highest only after 2 and 3 years [30]. On the other hand, in a cohort
of apprentice bakers, the incidence of all respiratory symptoms was higher in the
second year of training; the incidence of skin reactivity to occupational allergens
also increased from 4.6% to 8.2% between the first and second year in training
[12]. Differences in the time course of occurrence of these outcomes for these different populations of apprentices are difficult to interpret; they may be attributable to
differences in duration and intensity of exposure to the causative agent(s), or to the
varying pathogenicity of the allergens. Nevertheless, the implications for setting the
timing of surveillance programs are the same, and would be to screen for sensitization and symptoms in the first 2–3 years of apprenticeship.
The ‘allergic march’
It is generally believed that rhinitis precedes asthma [31]. There is some evidence
that rhinitis of occupational origin progresses into asthma [32, 33]. Cohorts of
apprentices can offer a powerful approach to verify the assumption of an allergic
march. However, the published data from apprentice studies have not yet provided
clear evidence to confirm this hypothesis. Indeed, results from the prospective study
of apprentice bakers conducted by Walusiak [12] showed that the latency period
for new nose and chest symptoms was almost the same; the diagnosis of occupational rhinitis (36/287) and of OA (25/287) by specific inhalation challenges were
concurrent in 25/36 individuals. For only 5/25 apprentices with confirmed OA was
it shown, during the clinical examination, that OA was preceded by allergic rhinitis,
which was not necessarily work-related, but present prior to entering the apprenticeship [12]. From a different perspective, in a prospective study among apprentice
animal-health technicians, the predictive values of work-related rhinitis symptoms
for the development of respiratory symptoms and of probable OA were estimated
at 9.0% and 11.4%, respectively; these rather low values failed to provide evidence
for the ‘allergic march’ [30]. Nonetheless, the length of follow-up of most studies
published since 1999 has been limited to the duration of the apprenticeship, which
does not exceed 3 or 4 years (see Tab. 1).
239
Denyse Gautrin and Jean-Luc Malo
Factors associated with asthma
The factors associated with asthma that are consistently reported in the cohorts of
apprentices are host factors assessed at baseline; some studies have evaluated the
role of ‘intermediate’ outcomes, such as skin sensitization for the development of
work-related symptoms. Exposure parameters have not been considered as much.
Factors at inception
The prospective cohorts of apprentices document host factors at baseline, which are
essential from different perspectives: first, for detecting the incidence of ‘endpoints’
that may already be prevalent before starting an apprenticeship (e.g., sensitization
to training-specific allergens and BHR), and second, for identifying determinants of
OA and associated features with knowledge of the sequence of events. In the following section, ‘Factors’ are regarded as ‘determinants’ or risk factors.
Atopy
Atopy evaluated by skin tests to common allergens is a determinant of skin sensitization to training-specific HMW allergens. Where ubiquitous allergens were
individually considered, the effect of individual allergens was shown; for example,
grass pollen for sensitization to flour [16, 29] and pets in the case of sensitization
to laboratory animals [21]. As shown in Table 1, atopy is an important determinant
for the other endpoints studied in apprentice cohorts exposed to HMW agents and
also in hairdressing apprentices [26]. However, investigators have mostly uncovered
a predominant role of individual aeroallergens.
Although in a smaller proportion, non-atopic subjects also develop work-related
sensitization and symptoms when exposed to HMW occupational agents. Interestingly, the factors associated with various endpoints vary according to the atopic
status; for example, rhinitis symptoms on contact with pets and skin sensitization
to pets were associated with work-related rhinoconjunctivitis symptoms in atopic
apprentices exposed to laboratory animals, while perennial rhinitis and having
a PC20 b 32 mg/ml were found in non-atopics [34]. In apprentice pastry makers,
atopic at inception, no other factor was associated with the incidence of workrelated rhinoconjunctivitis symptoms, whereas in non atopics symptoms of rhinitis
on contact with pets was the factor most strongly related [34].
Skin sensitization to the training-specific allergen(s)
In cohorts of apprentices, the prospective design offers the possibility of assessing
sensitization to training-specific agents at inception. A proportion showed signs of
240
Asthma in apprentice workers
immunological sensitization to laboratory animals [11] or flour [16] on early exposure during the apprenticeship; this may result from immunological cross-reactivity
with ubiquitous allergens derived from animal or plant species. Prior specific sensitization to baker’s allergens was related to incidence of work-related rhinoconjunctivitis symptoms in apprentice pastry makers [29] and of OA in apprentice bakers [12].
History of symptoms of allergy
Similar to studies in workers, a history of nasal, skin and chest allergic symptoms
were associated with work-related sensitization and symptoms. The summary
results of the cohorts of apprentices presented in Table 1 show that chest and rhinoconjunctivitis symptoms, on contact with pets or pollen or in any nonspecific
circumstances, are the main determinants of several endpoints, mainly work-related
symptoms of rhinoconjunctivitis, or are of similar importance as skin-prick atopy.
However, being highly correlated with atopy, they do not add as significant determinants in multivariate analyses.
History of allergic disease
Physician-diagnosed asthma (reported by the participants) was an important determinant of sensitization to latex in dental hygiene apprentices [23] and of workrelated respiratory symptoms in apprentice car painters [35].
Bronchial responsiveness
BR has only rarely been assessed at recruitment into apprentice cohorts. A PC20
equal to, or less than 32 mg/ml (measurable bronchial responsiveness) was associated with probable OA and probable occupational rhinitis [19, 20, 22].
Smoking and other host factors
Smoking status has been documented, but has not yet shown any association with
the development of the endpoints. Genetic studies are in progress to investigate
the link between selected polymorphisms and the development of sensitization to
training-related allergens and other hallmarks of OA.
Intermediate outcomes assessed throughout an apprenticeship
In cohorts of apprentice bakers, skin sensitization to pollens developed during the
apprenticeship was related to the development of sensitization to flour [16] and to
the onset of OA [12]. On the other hand, new sensitization to baker’s allergens was
241
Denyse Gautrin and Jean-Luc Malo
associated with work-related respiratory symptoms [18]. The role of intermediate
outcomes in the development of a work-related disease has now been explored
further in a long-term follow-up of cohorts of apprentices exposed to HMW agents
[36] and the main findings are summarized below.
Exposure
Although the period of apprenticeship spans only a few years, Kennedy and colleagues found an association between the duration of exposure to metalworking
fluids and the development of the combination of BHR and asthma-like symptoms.
Similarly, in apprentice animal-health technicians, the number of hours in contact
with rodents in the laboratory was an independent determinant of a new sensitization to laboratory animals, after accounting for an allergic diathesis [21].
Previous epidemiological and exposure assessment studies considering either
currently employed or retired welders were unable to account for a critical window of first-time exposure, which usually occurs during the apprenticeship. The
prospective study by El-Zein and colleagues [25] considered this early window and
found that being exposed to welding fumes and gases during apprenticeship, over
an average period of 15 months, was associated with pulmonary function changes
and the development of welding-related systemic and respiratory symptoms. The
concentrations of metal fumes present in the breathing zone of apprentice welders
were quantified for four common welding processes (shielded metal arc welding,
tungsten inert gas welding, metal inert gas welding, and flux cored arc welding).
Throughout the duration of the apprenticeship, 247 samples were gathered. The
findings suggested the presence of rather low concentrations of metals; iron seemed
to be the best marker. The low concentrations prohibited further analysis with the
outcome variables assessed in the epidemiological study [25, 37]. The low concentrations found could be explained in part by the short sampling time, depending on
the actual time the students performed welding operations on a given sampling day.
Another explanatory factor could be the presence of a probably well-functioning
general ventilation system (personal communication by El-Zein, PhD).
Apprentices probably experience a different exposure compared to the fully
trained workers because of disparities in training, experience and products used. We
know very little about exposure of apprentices and this really needs further exploration. We will then need to investigate the extent to which the risk of work-related
allergy and asthma increases with parameters of exposure during apprenticeship.
So far, evidence of exposure-response relationship between exposure and workrelated allergies in cohorts of individual at risk is scarce, even among workers. The
first long-term longitudinal study to address this question in workers showed an
increased risk of laboratory animal allergy (LAA) related to duration of exposure
to animals and work in animal-related tasks [38].
242
Asthma in apprentice workers
Assessment of selection bias
No apparent self selection into the apprenticeship due to prior sensitization to the
relevant allergen(s) was observed in three populations of apprentices (animal health
technology, pastry making and dental hygiene); i.e., the proportion of subjects sensitized to laboratory animals at inception did not differ between career programs [11].
However, a healthy worker effect was suspected in hairdressing apprentices, who
showed fewer respiratory symptoms and higher lung function values in comparison
with office apprentices upon starting their training [26]. In general, participation in
prospective studies has raised satisfactory interest among apprentices. However, the
characteristics of non-participants and reasons for declining to participate are worth
investigating in order to assess the presence and/or the magnitude of a potential selection bias. When non-participant baker apprentices to a Danish cohort study were
asked why they refused, reasons were fear of blood sampling and the time commitment to the follow-up study [39]. Attrition or selection out of the cohort may also, in
some circumstances, introduce a bias. Factors associated with quitting an apprenticeship may be associated with the health status before entering and during the training.
These factors were investigated in a cohort of apprentices exposed to HMW agents;
a history of hay fever before entering the apprenticeship was a mild, but significant
determinant. Among apprentices in animal health, quitting was associated with baseline sensitization to laboratory animals and symptoms of asthma during apprenticeship, but not with work-related respiratory symptoms [40]. Interestingly, in the same
cohort of apprentices, acquiring sensitization, symptoms or BHR during training did
not significantly influence the decision of pursuing a career in the same field. Indeed,
around 80% of the individuals chose a job related to their training, but those who
complained of work-related rhinoconjunctivitis symptoms during apprenticeship
tended not to have a job with a risk of exposure to sensitizers during the 8-year
post-apprenticeship span [36]. Radon and co-workers reported similar findings in a
prospective cohort study of nearly 5000 people, showing no association between an
atopic diathesis at baseline and subsequent choice of a job [41].
Long-term follow-up
A follow-up study of the Canadian cohort of apprentices exposed to HMW agents,
8 years after ending an apprenticeship in animal-health technology, pastry making
and dental hygiene was carried out between 2002 and 2006. This was the first prospective study of an inception cohort of apprentices after they entered a workforce,
regardless of whether or not their job was related to their training [36]. Of note,
this cohort is one of those where apprentices (also named students) attend specialized vocational training schools; they seek employment into a workforce only after
their 2–3-year training. The incidences of work-related skin sensitization, rhinocon-
243
Denyse Gautrin and Jean-Luc Malo
junctivitis, chest symptoms, and BHR were, respectively, 1.3, 1.7, 0.7 and 2.0 per
100 PY in individuals who had, at anytime during the follow-up period, held a job
related to their training (78%). These incidence figures were lower than those found
during the apprenticeship; i.e., 7.3, 12.9, 1.7 and 5.8 per 100 PY for the respective
endpoints. We hypothesize that the most vulnerable individuals acquire these features early after starting exposure to specific sensitizers. This is in agreement with
results from studies with a short-duration follow-up; however, these findings need
to be confirmed in other long-term follow-up studies. Of interest, a high proportion
of apprentices who had developed these outcomes during training were in remission
at the follow-up assessment, even if they were still working in the same field (i.e.,
67%, 65%, 71% and 53% for work-specific skin sensitization, rhinoconjunctivitis
symptoms, chest symptoms and BHR, respectively); and more so in participants with
a work history not related to their apprenticeship (i.e., 80%, 76%, 75% and 86%).
Several clinical, immunological and functional characteristics present at inception
of the cohort or developed during the apprenticeship were found to be significantly
associated with incidence (post-apprenticeship) of the endpoints listed above or with
remission of those acquired while training. Clinical determinants acquired during the
apprenticeship included non-work-related respiratory symptoms for later incidence
of work-related chest symptoms and BHR, as well as nasal or conjunctival symptoms at work for a later incidence of BHR. In this cohort, new cases of probable OA
(defined in ‘Investigated outcomes’ above) were identified: 28 among animal-health
technicians and 2 among dental hygienists during their training. Of the 23 evaluated
at the 8-year follow-up, two had left the field and no longer showed the features of
probable OA, while 7/21 had persistent probable OA. Among 201 individuals at risk
and still working in the same domain, 3 developed probable OA.
Other long-term follow-up studies have been conducted in settings where the
apprenticeship was undertaken in the workplace. A retrospective cohort study of
laboratory animal workers used pre-employment screening data to assess the incidence of LAA symptoms in “naïve” individuals at the time they were accepted for a
job at a Dutch research institute [42]. It was shown that the risk of developing LAA
was still present after 3 years or more of exposure in contrast to an earlier notion.
A long-term longitudinal study in a large dynamic cohort of workers exposed
to laboratory animals (from a pharmaceutical company in North Carolina, USA),
although not an inception cohort in apprentices, has further described the natural
history of asthma and confirmed that laboratory animal allergy is a major risk factor for the development of asthma [43].
Conclusions
Cohorts of apprentices provide an excellent experimental model to follow the natural history of OA, as the stages preceding the first manifestations of asthma can be
244
Asthma in apprentice workers
assessed prospectively in addition to the prognosis of the disease itself or associated
features or pre-clinical manifestations after interruption or diminution of exposure.
Extensive assessment of baseline clinical, immunological, functional and psychosocial status, before exposure to the causal occupational sensitizers begins, is possible.
Exposure to known causal agents can be well characterized, both qualitatively and
quantitatively, and very importantly, its variation in intensity and duration over
time.
Studies of prospective cohorts of apprentices initiated before starting apprenticeship offer the possibility of following its members for long periods of time, as for
birth cohort studies.
Directions of future research
Long-term follow-up of cohorts of apprentices initiated in the early 1990s should
be encouraged and supported.
Research on on-going and especially new cohorts should encompass an improved
identification of the stages of the disease and of its determinants such as:
- Better evaluations of environmental factors and exposures that may influence,
potentiate, or attenuate the effect of occupational sensitizers on the development
of asthma, e.g., the general urban versus rural environment, concomitant exposure to endotoxins, ozone, SO2, solvents, or any relevant contaminant.
- Use of available tools to sample induced sputum to measure markers of disease.
- Measurements of exhaled NO.
- Better and more refined biological markers including: genetic polymorphisms,
markers of inflammation including inflammatory cells, chemotactic factors and
mediators of activation for these cells, and markers of remodeling such as matrix
metalloproteinases.
- New genetic investigations to gain a better understanding of possible changes in
genetic markers or their expression as a result of a specific environmental exposure.
- Psychosocial determinants.
Although apprentice cohort studies were primarily designed to study the natural
history of OA, the data now available can be used to develop prognostic models
for sensitization to occupational allergens and other markers of asthma during the
apprenticeship. The models would be based upon host characteristics at baseline,
outcomes assessed prospectively and characteristics of exposure as predictors. By
determining the individual probabilities of developing asthma and related endpoints, such models may serve to advise young people in their career orientation and
support surveillance programs targeted towards individuals at high risk.
245
Denyse Gautrin and Jean-Luc Malo
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127–32
Management of an individual worker with occupational asthma
Sherwood Burge
Heart of England NHS Foundation Trust, Birmingham Heartlands Hospital, Bordesley Green
East, Birmingham B9 5SS, UK
Abstract
The aim of management of an individual with occupational asthma is to preserve their health and
wealth, preferably to leave their employer in business, and to prevent other workers from developing occupational asthma. To do this a confident diagnosis must be made. Occupational asthma
should be suspected when asthma symptoms improve on days away from work or on holiday.
As these questions have many false-positive answers, the diagnosis needs objective confirmation.
The most appropriate first test is to carry out good quality peak flow measurements every 2 hours
for about 3 weeks during periods of usual work exposure. Specific IgE is helpful for most highmolecular-weight allergens, and can be used to monitor allergen avoidance. Specific bronchial challenge testing is required in new or difficult situations. Non-specific bronchial hyperresponsiveness
is not sufficiently sensitive to use as a screening test for those requiring further investigation. Once
a diagnosis has been made workers should be separated into those in whom further (usual level)
exposure is unlikely to cause further deterioration in their asthma (mostly those with acute irritantinduced asthma) and those who are sensitised to a workplace agent in whom further usual level
exposure commonly leads to deteriorating asthma. There is a hierarchy of control methods when
exposure must be eliminated or substantially reduced, going from substitution, source exposure
control and individual protection. Examples of each strategy are given. The availability and scope
of compensation schemes also affect management; some facilitate re-training and ensuring income
preservation much better than others. Successful management nearly always involves cooperation
between the affected worker, their employer and their compensation scheme. An accurate clinical
diagnosis is a requirement for all of these.
Introduction
The aim of management of an individual with occupational asthma (OA) is to preserve their health and wealth, preferably to leave their employer in business, and to
prevent other workers from developing OA. There is good evidence that, in general,
removal from exposure within the first year of work-related symptoms leads to a
better prognosis than that of those who remain exposed [1–7]. Also, those who have
reduced exposure generally do worse than those with no exposure at all [4, 8–12].
Within this generalisation, however, are individual workers who remain exposed
Occupational Asthma, edited by Torben Sigsgaard and Dick Heederik
© 2010 Birkhäuser / Springer Basel
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Sherwood Burge
and symptomatic, but in whom the severity of the disease does not progress (similar
to a person with non-OA who remains exposed to mites or animals to which they
are sensitised). The management of the individual worker depends crucially on the
context in which you are working (as the treating Physician or the Occupational
Physician) and the compensation system within which you work.
As the treating Physician your responsibility is to the individual worker. Not
all workers will allow you to contact their workplace, for which they need to give
consent. In my practice, about one third of all new patients with OA refuse consent
to contact their workplace, at least in the initial part of their management. They are
often worried that they will loose their job, which at least in the UK is common.
Under these circumstances, all you can do is give advice to the individual worker
about diagnosis, the likely poorer medical outcome if exposure continues and offer
follow-up.
For the majority, satisfactory resolution of OA requires cooperation with the
workplace, preferably via an Occupational Physician. As an Occupational Physician, you may be in an even more difficult position as again you have a duty of
confidentiality but also a duty to protect individuals from harm in the workplace.
The choices available to eliminate or reduce exposure, in descending order of
preference, are:
-
-
-
-
Remove the causative agent from the workplace (substitution); solves the problem for the index case and prevents further cases.
Relocate the index case to an area without exposure to the causative agent;
leaves others exposed and needs careful monitoring to make sure relocation is
successful. Re-exposure when getting to the new workplace, toilets, meal breaks,
etc., is common. The causative agent needs enclosure to one part of the workplace. Relocation often involves a less satisfactory job (e.g. to a labouring job in
an outside yard).
Substantial reduction of exposure to the causative agent; this is a good solution to reduce further sensitisation but has usually to be done very efficiently to
reduce exposure sufficiently in the index case to prevent symptoms. Enclosure
of the source with extraction to the outside would be an example. Extraction
through a filter to the workplace is often less satisfactory and requires careful
maintenance of the filters.
Respiratory protective equipment (RPE); regarded as a last resort, often satisfactory for short intermittent exposures. If needed for the whole work shift it has
to be organised and maintained to prevent exposure. This involves donning and
removing outside the work area, maintenance by someone else wearing their
own RPE, and correct use and replacement of filters. All of this is more difficult
to achieve than it may seem.
Terminating employment; this should achieve removal from exposure, at least
temporarily. This could be a good option if there is a compensation scheme
250
Management of an individual worker with occupational asthma
with a large re-training element, it would then appear much higher up the list of
options. Without access to good re-training, the affected worker is often left with
the option of unemployment, or getting a similar job to the one causing OA. This
may involve concealing the original diagnosis and re-exposure to the original
cause; often, however, in a better maintained workplace with lower exposures
than before.
I illustrate the options using data needed for diagnosis and management. A fuller
account of the tests illustrated here appears in the chapter by A. Cartier.
Evidence-based guidelines
There are many guidelines for the management of OA, but only two so far
are based on a critical evidence-based review. The British Occupational Health
Research Foundation (BOHRF) is a charitable body; it commissioned the first
review concerning the occupational health aspects of the prevention, identification and management of OA. After identification of specific questions, there
was a systematic search of all published, methodologically sound and original
scientific studies, with each publication rated for the strength of the evidence plus
a narrative overview by agreement between two experienced and independently
minded reviewers. Where reviewers disagreed about the score of the paper or its
relevance to this research, they discussed it to reach resolution. Where resolution
was not achieved, a third reviewer was involved. Evidence tables were made for
each pre-defined question and formed the basis to formulate evidence statements
and recommendations. The evidence statements related to the management of an
individual are as follows:
- What is the prognosis of OA?
Generally, OA is reported to have a poor prognosis and to be likely to persist and
deteriorate unless identified early and managed effectively. The symptoms and functional impairment of OA caused by various agents may persist for many years after
avoidance of further exposure to the causative agent.
-
Which factors increase the probability of a favourable prognosis after a diagnosis of OA?
Complete avoidance of exposure may or may not improve symptoms and bronchial
hyperresponsiveness. Both the duration of continued exposure following the onset
of symptoms and the severity of asthma at diagnosis may be important determinants of outcome. Early diagnosis and early avoidance of further exposure, either
by relocation of the worker or substitution of the hazard offer the best chance
of complete recovery. Workers who remain in the same job and continue to be
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exposed to the same causative agent after diagnosis are unlikely to improve and
symptoms may worsen. The likelihood of improvement or resolution of symptoms
or of preventing deterioration is greater in workers who have no further exposure
to the causative agent. The likelihood of improvement or resolution of symptoms
or of preventing deterioration is greater in workers who have relatively normal
lung function at the time of diagnosis, who have shorter duration time between first
exposure and first symptom, or a shorter duration of symptoms prior to avoidance
of exposure.
- What evidence is there for benefit of redeployment within the same workplace?
Ideally, complete and permanent avoidance of exposure is the mainstay of
management. In practice, workers may reject this advice for social or financial
reasons. If it is possible to relocate the worker to low or occasional exposure
work areas, he or she should remain under increased medical surveillance. Where
present, specific IgE can be monitored, although this has not been shown to
affect outcome. Redeployment to a low-exposure area may lead to improvement
or resolution of symptoms or prevent deterioration in some workers, but is not
always effective.
-
What evidence is there for the benefit of the enhanced use of respiratory protective equipment?
Once sensitised, a worker’s symptoms may be incited by exposure to extremely
low concentrations of a respiratory sensitiser. Respiratory protective equipment is
effective only insofar as it is worn when appropriate, that there is a good fit on the
face and proper procedures are followed for removal, storage and maintenance. The
few studies that investigate the effectiveness of respiratory protective equipment are
limited to small studies in provocation chambers or limited case reports. There are
no large studies of long-term outcome. Air-fed helmet respirators may improve or
prevent symptoms in some but not all workers who continue to be exposed to the
causative agent.
- What is the impact of OA on employment?
There is consistent evidence derived from clinical and workforce case series in a
limited number of countries that about one third of workers with OA are unemployed after diagnosis. The risk may or may not be higher than among other adult
asthmatics, although this has been examined in only three studies. The risk of
unemployment may fall with increasing time after diagnosis. There is consistent
evidence that loss of employment following a diagnosis of OA is associated with
loss of income. In comparison with other adult asthmatics those whose disease is
related to work may find employment more difficult. Approximately one third of
workers with OA are unemployed up to 6 years after diagnosis. Workers with OA
suffer financially.
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Management of an individual worker with occupational asthma
- What is the effectiveness of compensation being directed towards rehabilitation?
There are no studies that have made direct comparisons between different systems
of rehabilitation either under different jurisdictions or within the same jurisdiction
at different times. Systems that incorporate re-training may be more effective than
those that do not.
- What is the effect of inhaled corticosteroids on recovery from OA?
A single small randomised-controlled trial has examined the effect of inhaled corticosteroids on the recovery from OA after cessation of exposure. Small but statistically significant improvements in some symptoms, peak expiratory flow (PEF) and
quality of life were reported.
These guidelines can be accessed interactively, allowing you to add further evidence
or comment on the existing evidence, at www.occupationalasthma.com/bohrf.aspx.
They are currently being updated. The Canadian evidence-based guidelines were
only concerned with the diagnosis of OA, and used statistical methods to calculate
the sensitivity and specificity of individual tests. They used specific inhalation testing
as the reference standard following a systematic review of literature regarding the
diagnosis of OA in which specific inhalation challenge testing was compared with
alternative tests [13]. The results complement the BOHRF non-statistical approach
and provide confidence limits for the BOHRF statements. The following conclusions were reached:
-
What are the sensitivity and the specificity of a normal measurement of nonspecific reactivity, while at work, in the diagnosis of OA?
Non-specific hyperresponsiveness had a sensitivity of 79.3% [95% confidence interval (CI) 68–88%] for high-molecular-weight (HMW) agents and 66.7% (95% CI
58–74%) for low-molecular-weight (LMW) agents. Specificity was 51.3% (95% CI
35–67) for HMW and 63.9% (56–71%) for LMW agents.
-
What are the sensitivity and the specificity of specific IgE testing in the diagnosis
of validated cases of OA?
Specific IgE had a sensitivity of 73.3% (95% CI 64–81%) for HMW agents and
31.2% (95% CI 23–41%) for LMW agents for which tests were available. Specificity was 79.0% (95% CI 50–93%) for HMW agents and 88.9% (95% CI 77–92%)
for LMW agents.
The highest sensitivity among LMW asthmagens occurred with combined nonspecific reactivity and skin prick tests (100%; 95% CI 74.1–100%). Specific IgE
and skin prick tests had similar specificities (88.9%; 95% CI 84.7–92.1%; and
86.2%; 95% CI 77.4–91.9%, respectively). For HMW agents, high specificity was
demonstrated for positive non-specific reactivity tests and skin prick tests alone
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Sherwood Burge
(82.5%; 95% CI 54.0–95.0%) or when combined with specific IgE (74.3%; 95%
CI 45.0–91.0%). Sensitivity was somewhat lower (60.6% and 65.2%, respectively).
While positive results of a single non-specific reactivity test, specific skin prick tests,
or serum-specific IgE testing would increase the likelihood of OA, a negative result
could not exclude OA.
Confidence in the diagnosis
The degree of confidence that you require for diagnosis depends on the consequences for the worker. For instance, if an individual may lose his or her employment
because of a diagnosis of OA, then a much greater degree of certainty is required
than if relocation is easy to a non-exposed job without loss of income or status.
Table 1 gives the sensitivity and specificity of the various diagnostic tests available.
Testing for specific IgE has been omitted as it is very variable from antigen to antigen, but in some situations (e.g. prick tests to ammonium hexachlorplatinate) can be
both sensitive and specific for OA [14, 15]. Specific IgE measurements can be very
useful for finding a specific cause for HMW agents once OA has been confirmed
by other means.
There is one study of workers with a good history of OA and negative specific
challenges, who subsequently had workplace challenges and serial PEF measurements [16]. OA was confirmed in 29%, and asthma or rhinitis (of any sort)
excluded in 34%.
Table 1. Sensitivity and specificity of different diagnostic tests for occupational asthma; averages from the BOHRF evidence-based review. Specific challenge tests were usually taken as
the gold standard [7].
Sensitivity %
Specificity %
History and examination
95
55
PEF before and after day shift ($ > 5 l/min)
50
95
Non-specific reactivity away from work ($ 3.2 times)
48
64
Serial PEF <4/day or < 3 weeks (Oasys score >2.5)
64
83
Serial PEF r 4/day and r 3 weeks (Oasys score >2.5)
78
92
Serial PEF r 4/day and r 4 work and rest days
(mean PEF rest days – workdays >16 l/min)
67
100
62–71
92
Serial PEF ABC (area between curves) r 15 l/min/hour
Workplace challenge
No comparative data
Specific challenge
Unknown but <100%
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Management of an individual worker with occupational asthma
Use of Oasys plotter of serial PEF measurements in diagnosis and management of workers with OA
If occupational exposure causes or exacerbates asthma, this must be measurable
with serial measurements of PEF or FEV1. The problems arise because the effects
of occupational exposure may be delayed, may increase with successive exposures,
and recovery may be delayed. The effects of work exposure needs separating from
those due to diurnal variation, treatment, non-specific exposures such as exercise,
infection and other allergen exposures. The Oasys plotter is a validated tool for
plotting and analysing serial measurements of PEF. Recording should be made at
approximately 2-hour intervals. For day shifts measurements on waking, arriving at
work, during each work break, leaving work, mid evening and bedtime, with most
importantly readings similarly spaced on days away from work. Each “days” plot
starts with the first reading at work, and continues until the last recording before
work on the next day, with special adjustments during shift changes (the day interpreter).
There are three validated methods of analysis of Oasys plotted records, with
different minimum data quantity requirements. The original Oasys score was based
on a discriminant analysis comparing a period of days at work with the preceding
and following periods away from work (a rest-work-rest complex) and its counterpart a work-rest-work complex. Complexes were scored from 1 (no evidence of a
work effect) to 4 (definite work effect). The complexes were summed with double
weighting for scores of 1 and 4; a mean of > 2.5 was found to be highly specific
for independently diagnosed OA. This analysis is tolerant of missing or mistimed
readings; its published specificity includes any prefabricated readings in the selfrecorded records. The minimum data quantity for optimal sensitivity and specificity
is r 5 complexes (about 3 weeks), r 3 consecutive days at work, r 4 readings/day,
no changes in treatment, with no respiratory infections and with typical exposures
during the record (see Figs 3 and 4 for examples).
The area between curves (ABC) score compares the mean value for each 2-hourly
segment between days at work and days away from work. Plotting hours from waking allows different shift patterns to be compared; the plot also separates days with
different work exposures. Accurate timing of the readings is more important for this
analysis; minimum data quantity is r 8 readings/day with r 8 workdays and r 3 days
away from work. The specificity was 92% and sensitivity 62–71% with the ABC
score r 15 l/min/hour for day-shift work (see Fig. 1 for example).
The final method compares the mean PEF on days away from work with those
on workdays, after day interpretation. The upper 95% CI for asthmatics without
OA, and asymptomatic workers exposed to high levels of irritants (grain dust) is
16 l/min. Values over this have a sensitivity of 70% for OA. The minimum data
quantity for this analysis has not yet been assessed. Oasys analyses are supported by
the website www.occupationalasthma.com.
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Sherwood Burge
Figure 1.
Mean 2-hourly value of PEF on 7 workdays and 6 days away from work. The period at work
is shaded (centre section always at work, end panels sometimes at work). Taken from an
Oasys Utilities plot; the bottom panel shows the time in 2-hour blocks, the number of readings on workdays (left) and rest days (right) and the difference between work and rest days.
The graph is only plotted when there are at least three measurements at each data point.
The area between the curves (ABC) score is 7 l/min/hour. A score >15 is required to show a
significant work effect.
Is the current work exposure causing temporary or permanent damage to
the lungs?
Workers with acute irritant-induced asthma (toxic asthma) have asthma induced
by a single large exposure but have not become sensitised to the agent and should
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Management of an individual worker with occupational asthma
be able to tolerate low levels of exposure to the same agent without problems.
Although they are now asthmatic, most will be able to remain in their original jobs.
Heightened surveillance would then be required.
Workers with work-aggravated asthma who have regular deterioration with
work exposures and improvement away from work, or workers with OA from
any mechanism will need careful assessment before continuing exposure is recommended. Evidence shows that the majority (but not all) of these will have deteriorating lung function and the longer the symptomatic exposure continues, the worse
the long-term prognosis. There are, however, individuals who have regular asthma
in relation to work exposures who show no identifiable long-term consequences.
At the moment we do not know how to identify those with a good prognosis from
those with a poor prognosis at the time of diagnosis and it is only after prolonged
follow-up that the situation becomes clear. There does not seem to be a relationship
between the type of agent, the magnitude of reaction to the occupational agent,
atopy, smoking or treatment between those with good and poor prognoses. Those
with a low lung function at presentation are amongst those with a poorer prognosis
but these compose the minority of all those with OA.
A security guard with acute exposure to diesel fumes
A previously well 46-year-old security guard was locked in the back of a 16-ton
security van that was stuck in a traffic jam on a busy intercity road on a foggy
November morning for 90 minutes, while the diesel exhaust was escaping into his
compartment through a ruptured exhaust pipe. His eyes started to smart and run, he
felt tired, he had difficulty breathing, wheeze and a hoarse voice. On being released
he vomited, and was taken to the Accident and Emergency department where he
was found to be wheezy and breathless. He was awake during the next 2 nights with
wheeze and breathlessness, and returned to work on the third day. Six days later he
saw his General Practitioner who found him wheezy and breathless, PEF was 275 l/
min. He was given prednisolone and salbutamol and had non-specific reactivity to
histamine within the asthmatic range. For the next year he woke twice each night
breathless, was wheezy for 2.5 hours each morning, and missed much time from
work. He found it difficult to carry much money upstairs. He continued to smoke
35 g pipe tobacco/week. His employer wondered whether his current job was detrimental to his health. He kept serial measurements of PEF, the mean value for each
2-hour period for work and rest days are shown in Figure 1.
The plot shows that he wakes with a low PEF, which improves similarly whether
at work or not. He has developed acute irritant-induced asthma, but continuing work
is not associated with worse PEF. The problems he is having at work are likely to be
due to his underlying asthma, provoked by exercise. Increased asthma treatment to
help him cope with the exercise and carrying is likely to be the best way forward.
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Sherwood Burge
Removal from exposure or reduction of exposure?
There are some individuals where reducing exposure is sufficient to abolish workrelated asthma and some where complete removal from exposure is required. For
those with the most extreme sensitivity, contact with workers with antigen on their
clothes outside the workplace may be sufficient to provoke asthma. Cases of this
sort have been shown in laboratory animal workers, isocyanates and complex salts
of platinum amongst others. Antigen may be taken home on the hair and clothes of
the worker and contaminate the home environment as well (shown with laboratory
animal workers) [17].
Substitution
The best solution is to remove the offending agent completely from the workplace
so that the individual sensitised worker can continue with employment and others at
work no longer run the risk of sensitisation. There are a number of good examples
of this, including the removal of isocyanates from an undercoat in a steel-coating
works [18]; the substitution of glutaraldehyde with non-aldehyde sterilising agents
for endoscopes and its removal from x-ray developer; the substitution of latex
examination gloves for vinyl or nitrile gloves and the substitution of charged platinum salts with tetraamine platinum dichloride in the manufacture of catalytic car
exhausts [15]. Sometimes technological changes may remove the need for particular
exposures, for instance moving to cell cultures from live animal work, or moving to
digital radiology from developed x-ray films. However, sometimes an agent causing
OA is replaced by another for which there is no information, which subsequently
turns out to be a sensitising agent. This for instance has occurred particularly with
isocyanates, where originally methylene diphenyl 4,4’-diisocyanate (MDI) was proposed as a safer substitute for toluene diisocyanate (TDI); subsequently MDI has
been shown to be a major sensitising agent. The replacement of diisocyanates with
pre-polymers and partially reacted isocyanate products has also not solved the problem. Recently, hydroxylamine used to replace glutaraldehyde for paper de-inking
has caused OA [19].
Two workers coating steel sheet with PVC
Two workers in a factory coating steel sheet with a PVC coating presented to
their occupational physician with symptoms suggestive of OA, subsequently
confirmed with serial measurements of PEF. Both worked on the paint line where
a continuous steel strip was passed through rollers; first an undercoat and then
the PVC topcoat were applied, passing through ovens after each application.
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Management of an individual worker with occupational asthma
The undercoat was known to contain epoxy resins, acrylics, phenol formaldehyde and chromates, all possible causes of OA. A survey of the 241 workforce
identified symptoms suggestive of OA in 9.5%, a further 28.5% had less specific
work-related respiratory symptoms. Workers on any part of the paint line were
at increased risk compared with workers in other parts of the factory. Unknown
to the factory, TDI had been added to the undercoat 8 years previously. The two
index cases had positive specific challenge testing to TDI. (Fig. 2) The isocyanate
was removed from the undercoat and the workforce restudied 1 year later. No
new cases of OA had occurred, and nocturnal waking from asthma was reduced
in both those with symptoms originally suggestive of OA (from 55% to 18%),
but also in those with less specific symptoms (from 40% to 16%). This outbreak
shows the need to make a specific aetiological diagnosis with a challenge test,
and the value of removing the causative agent, extending beyond those originally
thought to have OA [18].
Figure 2.
Specific challenge tests to toluene diisocyanate (TDI) in an index worker in a factory coating steel sheet, showing a late asthmatic reaction to TDI. As there were several other possible causes of occupational asthma (OA) in the workplace, the specific challenge allowed
the precise cause of the outbreak to be identified and the correct remedial action to take
place.
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Reducing exposure
There is reasonable evidence that higher levels of exposure lead to greater levels of
sensitisation for most agents. Reducing inhalable exposure to an occupational allergen should be a primary aim of control. This is best done by engineering methods
and there are good examples of this in the literature. For instance, biological detergents were a major cause of OA. Inhalable levels of the detergent enzymes have been
reduced by reformatting the powder into a pelletised version, which is less dusty,
enclosing the process particularly in the packing areas and by local exhaust ventilation [20]. Lapses in this control process particularly related to compression into tablets have resulted in a recent outbreak of OA in a biological detergent factory [21].
Detergent enzyme sensitisation can be measured with skin prick tests or specific IgE
assays, which can be used for surveillance. There are more detergent workers with
sensitisation than with OA, but controlling sensitisation should control disease.
Respiratory protective equipment
This is regarded as the last method for exposure control and requires substantial
attention to detail to make it effective. Unpowered masks are difficult to breathe
through as the work of drawing the air through the filter needs to be done by the
worker and few are acceptable for day-long use. Powered units either with an external air supply or air drawn through a filtering system give more acceptable protection but are unsuitable for workers who have to get into difficult places, for instance
maintaining machinery, and requires changing outside the work area and the cleaning and maintenance of RPE and air filters by somebody else wearing RPE.
Two workers manufacturing car engines
Figure 3 shows the Oasys PEF plot of a car engine manufacturer exposed to metalworking fluid aerosols. The first panel shows deterioration in 3/3 work periods and
improvement in 3/3 periods away from work in 2003. The Oasys score was 4.0; as
there were only two readings a day the sensitivity of this record is 64% and specificity
83% (the improvement from week to week invalidates interpretation of the rest–workday score). He was then relocated to an area of reduced exposure in 2004, although
improved, he continued to deteriorate on workdays and improve on days off work;
the Oasys score is now 4.0 and rest–workday difference 42 l/min (although there are
now six to eight reading/day the record is too short for optimal sensitivity/specificity). In 2005 he was wearing RPE in the same job, the record was probably normal;
however, there are only two readings on rest days which are inadequate for computer
scoring. Visual inspection of the whole record in this situation is preferable.
260
Management of an individual worker with occupational asthma
Figure 3.
Oasys plot of serial PEF of an car engine manufacturer exposed to metal-working fluid
aerosols. The top panel shows daily PEF diurnal variation. The centre panel shows the daily
maximum (upper dotted line), mean (middle horizontal bars) and minimum (lower dotted
line). Days away from work have a clear background, days at work a shaded background
(back hatching morning shift, forward hatching afternoon shift, cross hatching night shift).
The predicted PEF is the horizontal line at 559 l/min. The bottom panel shows the date, the
number of readings per day, the number of hours worked and comments. An explanation of
the findings is given in the text.
Figure 4 shows another worker from the same engine manufacturing shop who
kept serial PEF measurements before the metal working fluid was replaced. The left
panel shows an Oasys score of 3.91 and a rest–work difference of 45 l/min; this
fulfils all the criteria for an optimal record with Oasys score sensitivity 78% and
specificity 92%. After cleaning (centre panel) there is improvement, but the Oasys
261
Sherwood Burge
Figure 4.
Oasys plot of serial PEF in another worker exposed to the same metal-working fluid aerosols
as the worker in Figure 3. The first 4 weeks are before remedial action, the middle 4 weeks
after a complete clean and replacement of the metal-working fluid, and the right 4 weeks
while wearing full air-fed RPE. An explanation is given in the text.
score remains positive at 2.5 and the rest–workday difference 35 l/min. While wearing full air-fed RPE (right panel) the PEF has improved but still shows an Oasys
score of 3.56 and a rest–work difference of 32 l/min. Each change was associated
with an improvement in PEF, but even while wearing RPE he still deteriorated on
workdays and improved away from work showing that relocation away from exposure was required.
The role of compensation
The primary assessment of a worker with OA should separate workers who are
unlikely to be able to work again because of the severity of their disease or their
262
Management of an individual worker with occupational asthma
nearness to a normal retirement age and those who could work productively again,
provided that they are not exposed to the agent to which they are sensitised. Those
who are unlikely to work again are best handled by some sort of compensation to
make up for their loss of earnings.
Those who may work again often need re-training and have income preserved
during this period of re-training. There are only a few schemes in the world where
compensation includes a major resource for re-training and, even in these, only a
minority have substantial re-training. Good examples come for Quebec and Finland.
If re-training or preservation of income is assured through a compensation
scheme, it is much easier to remove somebody from exposure than for a similarly
affected worker who is not eligible for compensation in a particular country. For
instance, in some countries, OA is only recognised to a limited list of agents and if
a worker has the same disease from an unrecognised agent, removal from exposure
may lead to unemployment and no extra income at all.
Heightened surveillance for relocated workers
Any worker who continues in the workplace with possible exposure to the agent
to which they are sensitised needs heightened surveillance, which should at least
include a questionnaire and spirometry. If the OA is via an IgE mechanism, measuring the IgE serially should allow continued exposure to be monitored as specific IgE
has a relatively short half life and reduces with cessation of exposure. The interpretation of longitudinal data, particularly spirometry, is difficult, as measurement
error and spontaneous variability (95% CIs for FEV1 measured on two occasions
around 160 ml in good hands) is far higher than the expected decline of 25–30 ml/
year due to aging. A minimum of 5 years readings is usually required. The following show examples of IgE and FEV1 used in surveillance of relocated workers.
A laboratory scientist
A laboratory scientist developed urticaria, rhinitis and asthma that improved on
days away from work. Her job was mainly administrative but she did do some
hands on work for which she used latex gloves. She had a positive skin prick test
and specific IgE to latex, making latex the most likely cause of her symptoms. She
stopped wearing latex gloves herself but had little change in her asthma, or her
specific IgE, suggesting continuing exposure. Latex gloves were then replaced with
nitrile gloves in the whole laboratory, with improvement in her symptoms and a
reduction in her specific IgE to latex as shown in Figure 5.
263
Sherwood Burge
Figure 5.
Serial measurements of specific IgE to latex in a laboratory scientist with OA, rhinitis and
urticaria. It shows no reduction when she stopped using latex gloves personally, but an
exponential fall when latex gloves were removed from the whole laboratory, confirming
satisfactory avoidance of exposure.
A university professor with OA from rats
This professor developed severe asthma 8 years after starting work with rats and
mice. He was the only member of the department with an animal licence and was
responsible for bleeding mice occasionally. Following diagnosis in 1994 he stopped
working with animals, which were now transported in filter-top cages to reduce
exposure during movement. The results of trivial exposure to the rats when his
lecturer left and was not replaced is shown in Figure 6.
Taking action on serial measurements of lung function carried out during
medical surveillance is even more difficult as the measurement error and biological
variations are substantial in relation to suspected annual declines. SPIROLA is a
useful program for analysing serial measurements of FEV1 to detect abnormal FEV1
declines [22] (see examples in Figs 7 and 8).
SPIROLA
This program is available free of charge from National Institute for Occupational Safety and Health (NIOSH). It helps interpret longitudinal changes in FEV1
264
Management of an individual worker with occupational asthma
Figure 6.
Serial measurements of specific IgE to a rat urinary antigen in a university professor whose
research used with rats and mice. There was initially a satisfactory fall in specific IgE until
his lecturer left and was not replaced, leaving the professor to do very occasional teaching
sessions with rat exposure (30 minutes twice a year). His rat IgE stopped falling indicating
continuing exposure, levels fell again after retirement.
in individual workers, and detects excess decline when statistically significant. It
requires measurements over several years unless the FEV1 decline is very rapid,
for instance a decline of 400 ml in 1 year may be within the 95% CI for an individual. The interpretation of a result for an individual depends on the precision
of measurement for the group (and operators) from which the worker comes.
This is calculated by measuring the change in FEV1 percent predicted from two
measurements within 18 months, and calculating the standard deviation of this
change for the group. The 95% CI for this change is then calculated, which
reduces the longer the series of measurements for an individual proceeds. Over
the first 8 years of an individual’s follow-up, SPIROLA uses the limit of longitudinal decline (LLD) to determine whether or not the individual’s decline in FEV1
may be excessive. After 8 years of follow-up, the age at which the individual may
be expected to develop moderate-severe lung function impairment is taken into
consideration in the evaluation, which also shows how the last measurement has
increased or decreased the estimate of FEV1 decline. When the regression line
of FEV1 for an individual crosses the 95% limit of longitudinal decline, accelerated decline for that individual can be confirmed with confidence. The program
265
Sherwood Burge
Figure 7.
The SPIROLA plot of a cereal manufacturer. The round dots are the actual FEV1 measurements; the upper small dashed line the lower limit of normal; the upper solid line the estimated annual decline using linear regression; the lower heavy solid line the value for 60%
predicted at each age and the pale dotted line the lower 95% CI for the rate of FEV1 decline
using the centres precision estimate.
is supported by the website http://www.cdc.gov/niosh/topics/spirometry/spirola.
html.
The plot includes the actual FEV1 measurements, the lower limit of normal from
predicted equations, the estimated annual decline for the individual using linear
regression, the value for FEV1 that is 60% of that predicted at each data point, and
the lower 95% CI for the rate of FEV1 decline for the individual using the centres
precision estimate (Fig. 7). After 5 years of measurements, SPIROLA also plots the
effect of the last measurement on the calculated FEV1 slope, and FEV1 decline calculated on the last 8 years measurements only, allowing the detection of a change
in slope, for instance after the development of sensitisation to a workplace agent
(Fig. 8).
266
Management of an individual worker with occupational asthma
Figure 8.
SPIROLA plot of the same worker extended for 6 years after relocation away from thiamine
exposure, while working as a fork-lift truck driver in the stores. The upper panel shows
whether the last measurement has altered the calculated FEV1 slope (upper line), and FEV1
decline calculated on the last 8 years measurements only (lower line). There is a clear
improvement on relocation away from thiamine exposure.
A manufacturer of breakfast cereals
A 45-year-old non-smoking manufacturer of breakfast cereals developed rhinitis
shortly followed by asthma that improved away from work but was only worse
on some workweeks. He was under regular medical surveillance because of his
exposure to wheat and maize, which are recognised respiratory sensitisers. He was
removed from exposure to wheat and maize and continued to have annual spirometry. His FEV1 continued to fall. His annual FEV1 was plotted with SPIROLA and
is shown in Figure 7.
His estimated FEV1 decline crosses the 95% CI at the age of 49. It was now
clear that relocation had failed and that the standard of proof for the diagnosis of
wheat asthma based on history and PEF readings was insufficient. Interestingly, IgE
to wheat had been negative initially, but wheat asthma sometimes occurs with a
267
Sherwood Burge
Figure 9.
The results of specific bronchial challenge testing to nebulised thiamine showing a dual
asthmatic reaction.
negative IgE. At this point he was investigated with specific challenge tests, which
showed no reaction to wheat but a dual asthmatic reaction to thiamine, sprayed
onto the cereals for added nutritional value (Fig. 9). He was then removed from
thiamine exposure aged 50 and continued with annual spirometry while working
as a fork-lift truck driver in the stores. The updated SPIROLA plot is shown in
Figure 8.
Treatment
Treatment should be of benefit to those with OA in the same way as in non-OA.
There is pressure to treat rather than investigate when the patient first presents.
Treatment rarely if ever fully controls OA; it is much better to validate the diagnosis
of OA or non-OA first before starting (or increasing) treatment as the diagnostic
tests are less sensitive when more treatment is being taken [23]. If a worker elects to
remain exposed to the causative agent usual asthma treatments should be used. The
proportion of non-eosinophilic asthma is probably greater in OA caused by LMW
molecules than in non-OA [24], but as yet there are no studies which have investigated the benefits of inhaled corticosteroids in occupational asthmatics separated
into eosinophilic and non-eosinophilic variants. The use of anti-IgE therapy would
be particularly interesting in IgE-mediated OA, but so far only one small controlled
268
Management of an individual worker with occupational asthma
trial has not shown abolition of urticaria, rhinitis and conjunctivitis due to latex
allergy [25].
Conclusion
Managing a worker with OA requires an understanding of the mechanism (particularly the distinction between acute irritant-induced asthma and OA due to
sensitisation). The basic tools for OA diagnosis; spirometry, serial PEF, specific
IgE, non-specific reactivity and specific challenge testing, may all be needed in the
management of a worker after the diagnosis has been made to arrive at the best
outcome. Leaving a worker unemployed because of medical intervention is a failure
of our management; it is the outcome in about a third of all those with OA [7].
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Social consequences and quality of life in work-related asthma
Olivier Vandenplas and Vinciane D’Alpaos
Service de Pneumologie, Cliniques de Mont-Godinne, Université Catholique de Louvain,
Yvoir, Belgium
Abstract
Work-related asthma can interfere with patient’s daily life, including professional, familial, and
social activities. Occupational asthma (OA) is associated with a high rate of prolonged work disruption and loss of income. Available information indicates that work-exacerbated asthma has a
negative socio-economic impact to the same extent as OA. The socio-economic outcome seems to
be predominantly influenced by professional and socio-demographic factors. Adverse professional
and economic consequences are more pronounced when workers have to leave their workplace
because of reduced possibilities for accommodation in unexposed jobs within the same company or
lack of effective retraining programs. The socio-economic outcome is also affected by the age and
the level of education of affected workers. There is growing evidence that work-related asthma is
associated with a lower quality of life than asthma unrelated to work.
Introduction
The workplace environment can cause the development of asthma through immunological or toxic mechanisms (i.e., occupational asthma, OA) and trigger asthma
symptoms in subjects with pre-existing or coincidental asthma (i.e., work-exacerbated asthma, WEA) [1]. There is growing evidence that the various forms of
work-related asthma contributes substantially to the global burden of asthma [2–4].
Asthma can cause a physiological defect (i.e., impairment) that may affect daily life
activities (i.e., disability), leading to socio-economic consequences and altered quality of life (QoL).
Asthma-related impairment can be quantified based on the degree of airflow
limitation, the level of nonspecific bronchial hyperresponsiveness to histamine/
methacholine, and medications required to control symptoms, as recommended by
the American Thoracic Society [5]. Although airway inflammation is a key feature
of asthma, there is little information on the relationship between inflammation and
impairment in work-related asthma. Recent studies have shown that airway inflammation may persist in a substantial proportion of subjects with OA several years
after avoidance of exposure, even in subjects with normal functional parameters [6].
Occupational Asthma, edited by Torben Sigsgaard and Dick Heederik
© 2010 Birkhäuser / Springer Basel
271
Olivier Vandenplas and Vinciane D’Alpaos
It remains unknown whether persistent inflammation is associated with higher rates
of asthma exacerbation and worse functional outcome.
Assessment of disability is a much more complex process, as it should take into
account the global impact that impairment may have on patients’ functioning.
Translation of physiological impairment into disability is affected by many nonmedical variables, including: job conditions, age, gender, socio-economic status,
emotional factors, and co-morbidities. In addition, the patient should be compared
to himself prior to the disease in terms of daily activities and QoL. The discordance
between physiological impairment and disability is probably best illustrated in OA.
Affected workers should be considered completely and permanently disabled in
terms of occupations that entail exposure to the sensitizing agent that caused OA,
even when they demonstrate little physiological impairment without such exposure.
Work-related asthma may, therefore, lead predominantly to disability rather than
physiological impairment [7].
This section reviews available information pertaining to the impact of workrelated asthma on the different components of the socio-economic burden, including health care utilization, work productivity, loss of income, and QoL [8, 9]. The
factors that determine the socio-economic outcomes are explored to identify potential targets for interventions aimed at minimizing the adverse consequences of the
condition.
Healthcare utilization
An analysis of the Ontario Workers’ Compensation Board data found that the rates
of hospitalization for respiratory diseases and mortality among subjects compensated for OA were similar to those observed in asthmatic subjects without workrelated asthma [10, 11]. However, recent data derived from the Quebec’s Public
Health Insurance Plan [12] indicated that subjects with work-related asthma visited
a physician or an emergency department because of their asthma and were hospitalized more frequently than asthmatic subjects without work-related symptoms. The
medical resource utilization decreased after removal from exposure to the causal
work environment.
Work productivity
Work disability is a key component for evaluating the consequences of a disease, as
it can lead to reduced earning capacity and socio-economic status. Health-related
work disability can take different forms, including reduced workforce participation
and employment rates, restrictions in job duties or working time, lost work days
(i.e., absenteeism), and impaired effectiveness at work (i.e., presenteeism) [7].
272
Social consequences and quality of life in work-related asthma
Follow-up studies of workers with OA have consistently documented that the
condition is associated with a high rate of work disruption (Tab. 1) [13–22], with
the lowest rates being reported from Finland (14%) and Quebec, Canada (25%).
The reported rates of unemployment among subjects with OA and WEA seem higher
than in the general population, although there is a need for further characterization
of the specific impact of OA as compared with asthma unrelated to work. Whatever
its etiology, asthma may be associated with substantial disability, including reduced
workforce participation [23, 24] and impaired work productivity [23, 25–29]. In
the only available study that compared OA with non-OA, the rate of unemployment
was similar in the two groups, whereas a reduction of income was more frequently
reported by subjects with OA (62%) as compared with those with asthma unrelated
to work (38%) [16]. These two groups were, however, not matched for the severity
of asthma and other relevant socio-demographic variables.
Table 1. Employment and loss of income in workers with occupational asthma
Country
No. of
subjects
Duration of
follow-up
(years)
Rate of
unemployment
(%)
Loss of
income (%
of workers)
Reference
UK
112
Median: 1.4
35%
Exposed:
44%
Unexposed:
74%
Gannon, 1993
[13]
Canada, BC
128
Mean: 4.8
41%
NA
Marabini, 1993
[14]
Canada, Qc
134
Range: 2–5
25%
NA
Dewitte, 1994
[15]
UK
87
5
39%
55%
Cannon, 1995
[16]
France
209
Mean: 3.1
34%
46%
Ameille, 1997 [17]
USA
55
Mean: 2.6
69%
NA
Gassert, 1998 [18]
UK
770
Range:
1.5–5.5
37%
NA
Ross, 1998 [19]
Belgium
86
Median: 3.3
38%
62%
Larbanois, 2002
[20]
Norway
496
Range: 2–6
49%
51%
Leira, 2005 [21]
Finland
213
Mean: 10
14%
NA
Piirila, 2005 [22]
NA, data not available; BC, British Colombia; Qc, Quebec
273
Olivier Vandenplas and Vinciane D’Alpaos
The number of work days lost by workers with work-related asthma while they
are still employed is unknown. It should be outlined that the time elapsed between
the onset of work-related symptoms and the diagnosis of OA is often very long
and the economic impact of lost work productivity during this period should not
be neglected. Although a substantial proportion of employed asthmatics (9–27%)
report a reduction in work performance because of their condition [25, 27, 30], presenteeism has never been specifically assessed in subjects with OA who are working
(either exposed or not to the offending agent). It is, however, conceivable that work
effectiveness may be more impaired in subjects who experience work-related asthma
symptoms than in subjects with asthma unrelated to work [25].
Estimating the financial impact of work-related asthma should also include the
cost incurred by employers for hiring and training new workers or for modifying the
workplace environment. Up to now, the impact of work-related asthma has never
been assessed from the employer perspective.
Earning capacity
A high proportion of workers suffering from OA, ranging from 44% to 74%, report
a substantial loss of work-derived income attributed to their condition (Tab. 1) [13,
16, 17, 20, 21].
The socio-economic outcomes of WEA have been explored in a few studies [16,
20, 31]. The rates of unemployment and income loss in subjects with WEA did not
differ significantly from those observed in subjects with ascertained OA.
The proportion of subjects with OA who benefit from a financial compensation
varies from 17% to 87% in European countries [13, 14, 16, 17, 20–22]. The cost
of compensation for OA seems largely unknown. In addition, the effectiveness of
compensation systems in minimizing adverse socio-economic consequences of OA
has never been evaluated. The disease-related loss of income incurred by workers
with OA seems to be offset by the granted compensation in a minority of affected
workers (22% of subjects in Belgium [20] and 44% of subjects in France [17]).
Psycho-social and quality-of-life impacts
Health-related QoL refers to the global consequences of asthma and its treatment
on physical, emotional, and social aspects of patients’ functioning [32]. Malo and
co-workers [33] found that subjects with OA, even when removed from exposure,
have a slightly but significantly worse QoL than those with non-OA matched for
the severity of asthma. More recently, the factors that determine the magnitude of
the impact of OA on QoL have been investigated in a large population of subjects
with isocyanate-induced OA in Finland [22]. This study found that “satisfaction
274
Social consequences and quality of life in work-related asthma
with life” was related to current employment and higher levels of asthma control.
The effects of exposure interventions on QoL have never been assessed prospectively. In a retrospective study of subjects with latex-induced OA, asthma-specific
QoL did not differ among subjects who avoided and those who reduced exposure to
latex gloves [34]. The impact of OA and WEA on QoL appeared quite similar after
removal from exposure to the offending environment [31]. A recent study, conducted among asthmatic member of a US health maintenance organization, compared
QoL in subjects with self-reported WEA and those with asthma unrelated to work
[35]. Participants with WEA had a lower QoL, especially pertaining to “mood disturbance”, “social disruptions”, and “health concerns”, even after controlling for
relevant covariates.
Determinants of adverse socio-economic consequences
Available information indicates that a number of occupational and socio-demographic factors can adversely affect socio-economic outcomes in workers with
OA. Financial consequences of OA are consistently more pronounced in workers
who avoid further exposure to the causal agent [13, 17, 20, 36]. A loss of income
has been more frequently reported by workers who are completely removed from
exposure to the causal agent (69–78% of workers) [13, 20, 36] than by those
who remain exposed (17–44% of workers) [13, 20, 36]. The median self-reported
reduction of income was 54% in workers who were no longer exposed and 35%
in workers with persistent exposure [13]. Only one prospective study compared
asthma severity, disease-related costs, and work-derived income after cessation or
persistence of exposure to various agents causing OA [36]. Complete avoidance of
exposure to causal agents resulted in a significant decrease in asthma severity and
in health care expenses, but also in work-derived income, as compared with persistence of exposure [36]. This is likely to account for the finding that about one third
of workers suffering from OA remains exposed to the causative agent [13, 14, 17,
20, 22, 36], with the notable exception of Quebec where all subjects are removed
from exposure with a low rate of unemployment (25%) [15]. There is some suggestion that reducing rather than eliminating exposure to sensitizing agents could be
considered a reasonably safe alternative that would be associated with fewer socioeconomic consequences. In a retrospective study of 36 subjects with latex-induced
OA, respiratory health outcomes improved similarly after reduction or cessation of
exposure to airborne latex, whereas reduction of exposure resulted in a substantially
lower impact in terms of employment and earnings [34]. Nevertheless, the longterm health effects of reducing exposure to other agents causing OA remain largely
uncertain [7].
The loss of income is generally higher in workers who have to change their
employer as compared to those who remain employed in the same company [17].
275
Olivier Vandenplas and Vinciane D’Alpaos
Unfortunately, in European countries, less than 20% of subjects with OA are relocated to unexposed jobs in the same company [13, 17, 20, 22], while this proportion seems somewhat higher (31%) in Quebec [15]. Interestingly, the lowest rates
of unemployment (14% and 25%) have been reported in countries (i.e., Finland
and Quebec) where a high proportion of workers with OA benefits from effective
retraining programs.
Socio-demographic factors that are associated with a worse economic outcome
include: unskilled jobs [13, 20], lower levels of education [17, 20], older age [14,
20], younger age [17], a lower number of economically dependent subjects [14], and
being employed in small-sized firms [17]. Worth noting is the fact that the severity
of asthma does not appear to be an important determinant of employment status in
subjects with OA [13–17, 20, 36, 37], with the exception of Finland. In the Finnish survey of workers with isocyanate-induced OA [22], employment was mainly
affected by the severity of asthma. These data suggest that the role of disease severity may become apparent only when socio-demographic factors are appropriately
minimized.
Conclusion
OA is associated with a substantial impact on employment, earning capacity, and
QoL. Interestingly, work disability is affected predominantly by socio-demographic
factors, while the severity of asthma plays only a minimal role. Accordingly, interventions aimed at reducing the psycho-social consequences of work-related asthma
should focus on retraining and accommodating affected workers to unexposed jobs.
However, cost-benefit analysis of preventive interventions would require more precise and quantified data on the relevant cost components [38].
Acknowledgement
This work has been supported in part by the Actions de Recherche Concertées de la
Communauté Française de Belgique and the Fonds Scientifique CESI.
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279
Prevention of work-related asthma seen from the workplace
and the public health perspective
Vivi Schlünssen1, Evert Meijer2 and Paul K. Henneberger3
1
School of Public Health, Department of Environmental and Occupational Medicine, Aarhus
University, 8000 Århus C, Denmark
2
IRAS, Institute for Risk Assessment Sciences, Division Environmental and Occupational
Health, Utrecht University, 3508 TD, Utrecht, The Netherlands
3
Division of Respiratory Disease Studies, National Institute for Occupational Safety and
Health, Centers for Disease Control and Prevention, Morgantown, WV 26505-2888, USA
Abstract
Work-related asthma (WRA) includes occupational asthma and work-exacerbated asthma. WRA
is by definition preventable. This chapter discusses available tools for prevention of WRA, divided
into primary and secondary prevention. For each tool, the available evidence for the effectiveness of the tool is summarized, and examples are provided. Primary prevention addresses healthy
workers or persons with asthma due to causes unrelated to work. The principal tool is control of
occupational exposure, reached by elimination or reduction in exposure, but vocational guidance
and pre-employment screening are also regarded as primary prevention tools. Secondary prevention addresses early detection of work-related sensitization or WRA to prevent further progression.
The principal tool for secondary prevention is medical surveillance. Prediction models represent a
promising new tool in medical surveillance; this tool is described here in general and by an example. To set priorities for the prevention of WRA, the monitoring of occurrence in populations as
well as in specific industries is crucial, and this chapter therefore briefly describes different sources
for surveillance data including sentinel reporting systems, population studies, and occupational
disease registers. In the future, focus should be on well-conducted intervention studies, improved
exposure assessment, improved medical surveillance (e.g., using prediction models) and good quality national surveillance programs.
Introduction
Work-related asthma (WRA) includes occupational asthma (OA) and work-exacerbated asthma (WEA) [1]. OA, or asthma caused by work, is the most common occupational lung disease in developed countries [2]. In addition, WEA, or pre-existing
or concurrent/coincident asthma worsened by work factors, is probably even more
prevalent and deserves increasing awareness due to the increase in asthma per se
during the last 20 years [3]. Concurrent or coincident asthma has onset during
employment but is not caused by conditions at work.
Occupational Asthma, edited by Torben Sigsgaard and Dick Heederik
© 2010 Birkhäuser / Springer Basel
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Vivi Schlünssen, Evert Meijer and Paul K. Henneberger
WRA is by definition preventable. The following chapter discusses available
tools for prevention of WRA, divided into primary (prevention of development) and
secondary (prevention of progression) prevention. Tertiary prevention, or management of WRA, is dealt with in a separate chapter.
Suggestions for evidenced-based guidelines for prevention and management have
recently become available for OA [4, 5]. For each tool, the available evidence for the
effectiveness of the tool is summarized, and examples are provided.
Prevention of OA and WEA is in general covered together. With regard to primary and secondary prevention, tools for preventing OA and WEA are in principle
identical. In order to set priorities for the prevention of WRA, the monitoring of
occurrence in populations as well as in specific industries is crucial. This chapter
therefore briefly describes different sources for surveillance data including sentinel
reporting systems, population studies, and occupational disease registers.
Primary prevention
Here primary prevention addresses healthy workers or persons with asthma caused
by reasons other than work. The aim of primary prevention is to prevent development of work-related sensitization and, most importantly, WRA. The principal tool
for primary prevention is control of occupational exposure, reached by elimination
or reduction in exposure.
As we consider prevention of both OA and WEA as primary prevention, vocational guidance and pre-employment screening are also described in this section.
Control of occupational exposure
According to Nicholson et al. [5], evidence based on well-conducted case-control
or cohort studies suggests that reducing airborne exposure reduces the number of
workers who become sensitized and who develop OA. In Table 1, different ways of
controlling exposure are given focusing on source, room, or person, in decreasing
order of preference.
In some industries comprehensive knowledge about determinants of exposure is
available. A classic example from healthcare is substitution of low-protein powderfree natural rubber latex (NRL) gloves or non-NRL gloves for powdered NRL
gloves. A well-conducted prospective cross-over trial in an operation room found
that the mean aeroallergen level was decreased from 13.7 to 1.1 ng/m3 on days
where low-allergen gloves were used [6]. Other examples are studies in bakeries
[7–9], wood industries [10–13], and hair dressing saloons [14], where for instance
work task, cleaning procedures, quality of ventilation systems, and work routines
determine the level of the exposure of interest.
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Prevention of work-related asthma seen from the workplace and the public health perspective
Table 1. Different ways of controlling exposure
The source
- Substitution for the harmful agent
- Enclosure, automation, or modification of the process
The room
- Ventilation
- Avoiding resuspension of the harmful agent (e.g., cleaning
procedures, work practices)
The person
- Personal respirators
- Administrative initiatives (reduce number of workers or duration of
work time close to the harmful agent)
Several epidemiological studies have documented dose-response relations
between high-molecular-weight (HMW) and low-molecular-weight (LMW) allergens and the occurrence of WRA or sensitization, e.g., in bakeries and flour mills
[15–18], lab animal workers [19–22], wood workers [23, 24], and isocyanate workers [25–27], strongly suggesting that control of occupational exposure is effective
in prevention of WRA.
Only a few studies have directly explored the effect of preventive measures on the
occurrence of WRA or sensitization. NRL is the single most common agent addressed
in primary preventive intervention studies, as reviewed by Lamontagne et al. [28]. The
NRL studies all explored the effect of changing from high-protein powdered gloves
to low-protein powder-free NRL or non-NRL gloves, upon either the occurrence of
NRL sensitization [29–31] or the occurrence of NRL asthma or NRL-related symptoms [31, 32]. None of the studies fulfilled strict criteria for good quality intervention
studies, i.e., they were observational studies without a randomized design and without a control group, but taken together they support assertions that substitution of
NRL greatly reduces NRL sensitization and the occurrence of NRL-related asthma.
Smith [33] describes an attempt to prevent bakers’ asthma in a UK food company. The intervention was a 5-year health surveillance program, and by no means
a strict intervention study. Among other methods, they aimed at decreasing the general total dust level to < 10 mg/m3, and the bread improver exposures to < 1 mg/m3,
to diminish exposure to mainly fungal amylases. They focused on information and
training, installation of local exhaust ventilation, and wearing of respirators during
handling of powdered bread improvers. During the 10 years following 1993, they
found a decrease in the annual incidence rates of symptomatic sensitization (mostly
flour and fungal amylase) from 2085 per million to 405 per million employees
per year from the first 5 to the second 5 years. They did not measure the possible
decrease in exposure from 1993 to 2003.
An ambitious intervention study was started in the Netherlands in the flour processing sector [9]. More than 900 personal measurements from four flour processing
plants together with a thorough collection of control measures were used to model
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Vivi Schlünssen, Evert Meijer and Paul K. Henneberger
the baseline exposure level and to rule out significant determinants of exposure. The
Dutch government and the flour processing sector association agreed to participate
in reducing exposure to flour dust. Dust reducing control measures were implemented in the different sectors along with monitoring of trends in exposure as well
as sensitization and symptoms in the sector-wide health surveillance system.
In Ontario, the Ministry of Labour introduced a preventive program for diisocyanates in 1983, consisting of a mandatory 0.005 ppm airborne exposure limit for
diisocyanates together with a medical surveillance program. Tarlo et al. [34] assessed
retrospectively workers compensation data from 1980 to 1993. They showed an initial increase in compensation claims, which was attributed to increased case finding
due to the medical surveillance program. The 50% decrease in accepted claims from
1991 to 1992–1993 was attributed to a combination of primary and secondary
prevention measures. When measured levels of diisocyanate were compared among
companies who had compensated claims for OA with companies without accepted
claims, the former were more likely to have had measured levels of diisocyanates
> 0.005 ppm [35].
In the detergent industry, the occurrence of sensitization among employees
apparently decreased dramatically from the late 1960s to the mid-1980s [36]. During this period the detergent industry association had published work practices, and
at the same time medical surveillance programs were introduced. Two publications
sponsored by major manufacturing companies described significant reductions in
the prevalence of OA after introducing granulated proteases [37, 38]. Unfortunately
neither study reported incidence rates. A Danish retrospective follow-up study
reports decreasing incidence rates from the 1970s to 1990s for sensitization (0.2 to
0.06 per person year), but not for allergic diseases (0.03 to 0.02 per person year)
among 1207 enzyme plant workers followed the first 3 year of their employment
[39]. Cullinan et al. [40] reported an outbreak of asthma in a modern detergent
factory that exclusively used encapsulated enzymes. As many as 90 (26%) of the
workers were sensitized to a least one detergent enzyme, and 7% had a confirmed
diagnosis of OA. Sensitization rate was clearly related to exposure level. This study
indicates that the use of encapsulated enzymes is insufficient to control exposure
and prevent enzyme-induced OA.
Case reports on OA caused by newly introduced enzymes [41, 42] highlight the
importance of careful surveillance after introduction of new agents in the workplace. In addition, exposure to enzymes has increasingly shifted from the detergent
industry to intermediate industries, e.g., the baking industry, where people are
exposed to enzymes in low-technology environments [15].
In the US, a major pharmaceutical company introduced a preventive program for
laboratory animal allergy (LAA) [43]. The program included education, engineering
controls, administrative controls, use of respirators and medical surveillance. During a 5-year period, the incidence rate of asthma decreased from 10% to 0%. In the
same period, the percent of workers using respirators increased from 86% to 100%
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Prevention of work-related asthma seen from the workplace and the public health perspective
(workers with LAA) and from 50% to 81% (workers without LAA). No data on
other specific preventive measures were available.
In the UK, Botham et al. [44] studied a retrospectively assembled cohort of new
employees working with laboratory animals. In 1981, an education program for
persons working with laboratory animals was introduced. From 1980 to 1984,
the annual cumulative incidence proportion of symptoms consistent with LAA
decreased from 44% to 16%, and this effect was at least partly attributed to the
educational program.
Use of respiratory protective equipment
There is only limited evidence, based on mainly two non-analytical studies, to support a reduction in the incidence of OA through the use of respiratory protective
equipment (RPE). Grammer et al. [45] investigated the effect of introducing RPE
devices among 66 newly hired workers in an epoxy resin producing factory using
acid anhydrides. Only 4 of the 66 workers did not use RPE. From 1993 to 1999 the
incidence rate of acid anhydride sensitization combined with respiratory symptoms
decreased from 10% to 2%.
In a new wood plant that uses diisocyanate, Petsonk et al. [46] prospectively
estimated respiratory health and work practices over a 2-year period. Workers who
indicated that they had briefly removed respiratory protection had a five times
higher prevalence of new-onset asthma-like symptoms, compared to individuals
who reported never doing this (25% versus 5%).
Vocational guidance and pre-employment screening
The main purpose of vocational guidance before job choice, and pre-employment
screening, is to avoid persons at risk being exposed to sensitizers or irritant work
exposures to prevent OA and WEA. According to Nicholson et al. [4] some evidence
supports the claim that screening criteria do an inadequate job of identifying potentially susceptible individuals.
Knowledge of the effect of vocational guidance on career choice among teenagers is sparse. In some countries, e.g., Germany, Denmark and Sweden, vocational
guidance is a well-established practice in primary schools, but only a few evaluations of the effects have been performed. In 1992 in Sweden, Bremberg et al. [47]
evaluated whether medical vocational guidance among chronically ill preliminary
school students (including asthma) had any impact on their choice of career. Only
5 of 235 students stated that vocational information from physicians and school
nurses had been important for their choice of career, and the distribution of job
choices among the chronically ill students did not differ from the job choices among
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Vivi Schlünssen, Evert Meijer and Paul K. Henneberger
all students. A German study [48] and a Swedish Study [49] longitudinally elucidated career choices among asthmatics. They found self selection into low risk jobs
to play a minor role in teenagers with asthma or allergy. This could indicate that
vocational guidance among teenagers has a limited impact or has not been given.
Knowledge about the quality and nature of vocational guidance and the impact on
career choices is not available.
The effectiveness of using personal risk factors in pre-employment screening is
low [21, 50–53], which has been very well illustrated by Sorgdrager et al. [54]. They
used data on personal risk factors (atopic history, eosinophil count, lung function)
and incidence of pot room asthma from a nested case-control study to estimate
indicators of effectiveness of pre-employment screening. They calculated the positive predictive value (PPV), number needed to test and number needed to reject on
a simulated population of 10 000 persons with high incidence rates (40 cases/1000
person-year) and 10 000 with low incidence (5 cases/1000 person-year) of pot room
asthma. The atopic history prevalence was 6–12 times higher among asthmatics
compared to controls depending on the incidence rate of asthma. In general, atopic
history was the most effective indicator. The PPV was 20% at high incidence rates,
and an even lower 7% at low incidence rates. At high incidence rates it was necessary to test 138 persons to prevent one case of OA, and for each prevented case
of OA 5 persons were rejected from the job. They concluded that the personal risk
factors were far from effective as a selection instrument.
There is an increasing focus on genetic testing for screening out susceptible subjects. Theoretically, genetic testing could be used for pre-employment screening of
OA. So far associations between particular mutations and asthma occurrence are
modest with low odds ratios. Thus, prediction of future occurrence is unlikely to
be effective. Furthermore, asthma is caused by multiple genetic and environmental
factors, and information obtained by a single gene test is limited for both diagnostic
and preventive causes. Taken together, genetic testing is currently not useful for
identifying susceptible subjects in pre-employment screening [55, 56]
In conclusion, screening out susceptible individuals for asthma seems to be inefficient, and it might discourage efforts to reduce risks and prevent diseases in the
general working population. Vocational guidance and pre-employment screening
should not be used to discriminate who should or should not get a job, but may be
valuable tools to give persons at risk, e.g., atopic persons, an informed view of their
chance of developing OA or work-aggravated symptoms.
Secondary prevention
Secondary prevention addresses early detection of work-related sensitization or
WRA in order to prevent further progression. The principal tool for secondary prevention is medical surveillance.
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Prevention of work-related asthma seen from the workplace and the public health perspective
Medical surveillance of work-related asthma
Individuals with high exposure levels to aeroallergens are more likely to have serious
respiratory complaints and disability than workers exposed at lower levels. Even at
very low levels a residual sensitization risk remains. Studies also suggest that the
risk for work-related respiratory diseases cannot be avoided completely by exposure
reduction [57, 58]. Although elimination of airborne allergens from the workplace
is the ideal approach, it may not be possible in many workplaces such as bakeries,
and animal care facilities. Even if a reduction of exposure has been shown feasible,
there is no known no-effect level, other than zero, that will prevent sensitization
in all exposed workers. As an example, the experience with NRL, involving the
substitution of powdered gloves with “powder-free” gloves, has shown a dramatic
reduction of new cases of contact urticaria among health care workers. However,
allergic symptoms and asthma remained, although at lower prevalences, after this
intervention [32, 59, 60].
The duration of symptoms while working was studied in Canada [60, 61]; the
results showed a significant period of time between symptom onset and diagnosis
of OA. The reported median time to the first suspicion of WRA by a physician was
1 year for WEA and 2 years for OA patients. The median time to a final diagnosis
of OA after the onset of work-related symptoms was 4 years. Patients with OA
waited on average 8 months (median 3 months) before discussing their symptoms
with a physician. Lower education level and household income were significantly
associated with an increased time to diagnosis.
Although exposure reduction may markedly reduce the incidence of OA, the
ongoing high rates of work-related allergic diseases and the long time to diagnosis of WRA reinforces the need for secondary prevention by medical surveillance.
Therefore, parallel to exposure reduction and exposure control, medical surveillance of the entire workforce should be conducted to detect early evidence of all
work-related allergic and respiratory diseases.
However, different problems limit the successful use of medical surveillance programs for the identification of WRA, because asthma is characteristically a disease
with exacerbations and remissions, and WRA may, therefore, be unnoticed. Selfreported symptoms and use of medication failed to identify WRA exacerbations as
determined by serial peak exploratory flow measurements [62]. Routine surveillance
programs in bakery workers showed that the use of questionnaire-reported respiratory symptoms could not discriminate bakery workers with and without clinical diagnosed asthma or specific IgE for baker-related allergens [51, 63]. In addition, disease
outcomes are not identical in different workplace circumstances with different allergen exposures. In the case of low-molecular-weight sensitizers such as diisocyanates,
the immunological mechanism and the respiratory health outcome are less clear.
Most of the evidence mentioned in the “Guideline for the prevention, identification, and management of occupational asthma” is, however, derived from (clinical)
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case-control studies. The estimates of sensitivity and specificity are, therefore, biased
by preferential referral of patients and distort the determination of predictive accuracies [64]. Besides, the predictive value of a test varies not only across different
populations but also within a particular study population, and consequently may
have different sensitivities and specificities [40, 65]. So, a generalized conclusion
that a medical questionnaire is not a sensitive instrument for diagnosing OA can
hardly be drawn.
The diagnosis of WRA is a phased and complex process that requires both the
diagnosis of asthma and establishment of the relationship with work. It can only be
made at an individual level in a clinical setting [1]. Medical surveillance programs
should, therefore, not focus on clinically established allergic respiratory diseases, but
on highly associated preliminary characteristics to identify workers at risk of having
a work-related (allergic) disease. Sensitization to occupational allergens is one of
these strongly related outcomes linked to OA and often the most appropriate preliminary characteristic that can easily be investigated. For occupations characterized
by HMW allergens, a logical approach is therefore to identify sensitized workers
first, followed by sequential diagnostic investigations only in these workers. Usually,
sensitized workers are detected when they present themselves to the occupational
physician with symptoms. However, for patients with WRA, only 6% consulted the
company doctor first [66]. So, to find all sensitized workers, the whole population
must be evaluated by a specific skin prick test (SPT) or IgE serology, which is less
efficient and will result in high expenses for occupational health services.
Traditionally, “standardized” respiratory questionnaires used in epidemiological studies and medical surveillance programs contain questions about general and
work-related respiratory symptoms, allergy, and asthma. Every answer to a simple
question, such as “do you wheeze”, can be considered as a test result. However, different questions often provide the same information because they are all associated
with the same underlying disorder, and thus mutually correlated. For the occupational physician it is relevant to know which questions are redundant and which
have true, independent additional predictive value for the presence or absence of,
for instance, sensitization. Assessing the results of a particular test in view of other
test results may even diminish its diagnostic contribution, simply because the information provided by that test is already provided by the other tests.
So far, none of the medical surveillance programs have made use of prediction
research-derived diagnostic models in which personal and work-related characteristics are applied to estimate the individual probability of the presence (diagnostic)
or occurrence (prognostic) of an outcome that is closely related to the disease(s)
of interest. After detecting workers with an elevated risk, sequential diagnostic
investigations are only necessary in these workers. So, by using a questionnaire
as a first phase instrument, the probability of the occurrence of sensitization can
be calculated and subsequently be followed by more advanced tests in the clinical
evaluation.
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Prevention of work-related asthma seen from the workplace and the public health perspective
Prediction research and risk stratification
A diagnosis of a disease is the consequence of interpretations by individual medical doctors of consecutive test results, estimating the probability of the presence of
a disease or other outcome of interest. As many test results generate more or less
identical information it is important to evaluate the independent and additional predictive value of a test given the presence of earlier information. Prediction research
offers a solution for this by using a multivariate approach that accounts for mutual
dependence between different test results. The information of every item is translated into a predicted probability of the chosen outcome. This technique provides
estimations of the probability of an outcome at present (diagnosis) or in the future
(prognosis). Prediction models applied in occupational health practice may therefore
enable occupational physicians to deal with uncertainties in considering workers at
risk of having occupational diseases. The main goal is to optimize risk estimation
at low costs, and may be the first step in the clinical evaluation and management
of WRA [67, 68]. The models may initiate counseling and interventions, and are
thus useful for identification of specific groups at risk. In Figure 1, a flow chart of
medical surveillance of WRA using scores is outlined.
Figure 1.
Medical surveillance of work related asthma (WRA). P (S+), prior probability of sensitization to aeroallergens; P(S+|LS), probability of sensitization conditionally a low score; OAD,
occupational allergic disease.
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Vivi Schlünssen, Evert Meijer and Paul K. Henneberger
An example of a prediction model in occupational health practice
Models to predict IgE sensitization have only recently been developed for workers
such as bakers and laboratory animal workers who are exposed to HMW allergens
[67–69]. The models were transformed into scoring rules with a restricted number
of questionnaire items with different weighing factors. In a medical surveillance
program among 5325 bakers in the Netherlands, a short questionnaire, containing
19 questions with four predictors for sensitization to wheat and/or fungal A-amylase
allergens, was used as a decision tool in considering workers at risk of WRA. The
results of the questionnaire were transformed into sum scores to predict the presence of sensitization in every individual worker as shown in Table 2.
Table 2. Predictors and Predicted probability for sensitization (wheat and or A-amylase)
among bakers
Score chart
Predictors
Answer
Score
“Have you ever had asthma in the past 12 months?”
If yes
2
“Have you ever had allergic rhinitis including hay-fever?”
If yes
2
“Have you ever had itchy and/or red eyes in the past 12 months?”
If yes
1
“Do you experience more of the following symptoms during work:
shortness of breath, chest tightness, itchy eyes, itchy nose, and/or
sneezing?”
If yes
1.5
Sum scores
Max
6.5
Sum score
0
1
2
3.5
4.5
5.5
6.5
Predicted probability (%)
9
14
20
31
42
53
64
The scores were used to split bakery workers into three groups with different sensitization risk: a high-risk group in which detailed clinical investigations were required
to set a diagnosis of WRA and other work-related allergies more accurately, an
intermediate group in which medical follow-up by occupational physicians was
essential for diagnosis and health protection, and a low-risk group comprising about
60% of the population in which medical investigations could be held back. The
results are shown in Table 3.
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Prevention of work-related asthma seen from the workplace and the public health perspective
Table 3. General characteristics and questionnaire responses across low-, intermediate and
high-score groups
Low score
(b 1.0)
Intermediate
score
(1.5–3.0)
High
score
(r 3.5)
Total
Participants, n (%)
3059
(57.4)
1282
(24.1)
984
(18.5)
5325
Work duration, mean years (SE)
13.8
(0.2)
11.7
(0.3)
12.9
(0.3)
13.1
(0.14)
Upper or lower respiratory tract
symptoms to common allergens (at
least 1 positive answer), n (%)
209
(6.8)
448
(35.2)
642
(65.8)
1299
(24.5)
Symptoms suggestive for NSBHR (at
least 2 positive answers), n (%)
24
(.8)
52
(4.1)
144
(14.9)
220
(4.2)
Use of medication to improve
respiratory complaints in the last 12
months (e.g. inhalants), n (%)
74
(2.4)
186
(14.6)
468
(48.1)
728
(13.7)
Doctor visit for allergic complaints in
the last 12 months, n (%)
134
(4.4)
197
(15.5)
379
(38.7)
710
(13.4)
Absenteeism due to allergic symptoms
in the last 12 months, n (%)
6
(0.2)
34
(2.7)
79
(8.2)
119
(2.2)
Change of function or task due to
respiratory symptoms, n (%)
16
(0.5)
19
(1.5)
83
(8.5)
118
(2.2)
The predicted probability of sensitization can be calculated as:
= 1 / {1 + EXP[ – (–2.32 + 0.92 s asthma + 0.90 s rhinitis + 0.46 s conjunctivitis
+ 0.62 s during work symptom)]}.
Workers with high scores showed the highest IgE sensitization rate to wheat and/or
A-amylase, and the highest rates in medication use, absenteeism, and doctor’s visits.
This example illustrates that by using a score chart to predict the sensitization
risk in workers exposed to HMW workplace allergens, a diagnosis of WRA can be
considered more effectively and efficiently in the initial phase of a medical surveillance program performed by occupational physicians at the worksite. Prediction
models based on IgE-mediated sensitization is not useful for LMW workplace
allergens. To our knowledge no prediction models for LMW-related OA has been
developed, but models based on bronchial hyperresponsiveness (BHR) could potentially be useful.
291
Vivi Schlünssen, Evert Meijer and Paul K. Henneberger
Use of public health surveillance data to stimulate, guide, and document
prevention of work-related asthma
Public health surveillance comprises more than the identification and counting of
cases. It is “the ongoing systematic collection, analysis, and interpretation of health
data essential to the planning, implementation, and evaluation of public health practices, closely integrated with the timely dissemination of these data to those who
need to know.” [70]. This section highlights examples of how public health surveillance has contributed to the prevention of WRA. While the examples are drawn
from experience in the United States and Canada, this does not mean that similar
surveillance activities are lacking in other countries.
Investigations of reported cases have identified the measures needed to prevent
the onset and/exacerbation of asthma in specific workplaces, benefiting the index
case, co-workers, and the employer. The Sentinel Event Notification System for
Occupational Risks (SENSOR) is a state-based surveillance program for occupational diseases that is coordinated by the National Institute for Occupational Safety
and Health in the United States. The SENSOR program in the state of Michigan
registered 446 cases of WRA from 416 different workplaces during 1993–1995
[71]. Inspections were conducted at 185 (44.5%) of these workplaces, and air sampling for known agents were conducted at 123 (29.6%). Many recommendations
or citations were issued as a result of the inspections: 60 for medical monitoring,
80 for engineering controls, 63 for air monitoring, 126 for hazard communication
program, and 71 for respiratory protection program [71]. These figures suggest
that workplace inspections stimulated by WRA case reports frequently identified
deficiencies that inhibited prevention.
Ongoing surveillance programs facilitate the identification of and response to an
increase in the number or severity of asthma cases. Deaths due to work-related diseases are powerful warnings for workers with similar exposures. The Fatality Assessment
and Control Evaluation (FACE) program identifies and investigates work-related
deaths in several states in the United States. The Michigan FACE (MIFACE) program
reported a worker who died after he sprayed an isocyanate-containing coating inside
a van [72]. This surface coating is normally sprayed onto the open cargo beds of
trucks, but in this case was applied onto the floor and up the walls of an enclosed
van. The MIFACE investigation revealed deficiencies in several factors that contributed to this unfortunate occurrence: product stewardship by the manufacturer of the
materials used by the case, engineering controls, company health and safety program,
and health care provider recognition that the asthma was work-related. The Michigan
Occupational Safety and Health Administration (MIOSHA) issued 11 citations to the
company. Also, MIOSHA initiated contact with over 100 other companies in Michigan that applied spray-on truck bedliners and provided educational and technical
assistance. The surveillance program’s expeditious investigation and dissemination of
the findings likely had a positive impact on asthma morbidity and mortality.
292
Prevention of work-related asthma seen from the workplace and the public health perspective
Surveillance data can also be used to document the impact of preventive interventions. In the province of Ontario in Canada, legislation was passed in 1983 that
required workplace monitoring of diisocyanate levels to maintain exposures within
acceptable limits, as well as medical monitoring of exposed workers. The impact of
this legislation was tracked using worker compensation data. The number of diisocyanate OA cases began to increase during the early 1980s, probably due to the
increased medical screening of exposed workers [34]. The number of claims peaked
in 1988–1990 and began to decline after that. Also, the cases were less severe as the
number declined [34]. This decline in the number and severity of diisocyanate WRA
cases was likely the result of many activities, including better control of exposures
at work, and increased and earlier recognition of disease.
Future developments
Most intervention studies are best characterized as “complex intervention studies”
consisting of several intervention components, where the actual change in exposure
is seldom monitored. It is therefore not realistic to assume that most future studies
will fulfill strict criteria for good quality single intervention studies. However, it is
desirable to put more effort into ongoing monitoring of changes in exposure. Many
companies and organizations do collect data continuously on exposure, exposure
determinants, and health outcomes. The use and extension of this valuable data
source could be improved by establishing a closer cooperation between companies
and experts in exposure assessment and occupational lung diseases.
There is still a need for development of more effective medical surveillance
programs, and predictions models are a promising attempt to achieve that goal.
A major future challenge will be to develop effective prediction models for LMW
asthma.
Collection of surveillance data is essential in planning, implementation, and
evaluation of the prevention of WRA. In the future it will be crucial to maintain
resources for ongoing surveillance programs, and it will be of equal importance
to initiate surveillance programs in countries where no surveillance data currently
exist.
Finally, an increased focus on education of workers and health professionals is
crucial to increase the possibilities for prevention of WRA.
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Prevention and regulatory aspects of exposure to asthmagens
in the workplace
Henrik Nordman
Finnish Institute of Occupational Health, Topeliuksenkatu 41 aA, 00250 Helsinki, Finland
Abstract
The consequences of occupational asthma (OA) in terms of health, quality of life and costs
incurred for the individual as well as society are considerable and make prevention worthwhile.
The majority of cases are caused by comparatively few major asthmagens, such as flour dust,
animal epithelium, natural rubber latex, and diisocyanates. A substantial reduction of these exposures is a realistic objective. It is important that preventive strategies are undertaken as concerted
actions by all actors involved, i.e. regulatory authorities, branch organisations and worker unions.
However, many asthmagens only cause occasional cases. Understandably, the prevention of these
will rarely be highly prioritised. Aggravation of any asthma by non-specific exposures at work
(work-exacerbated asthma, WEA) has turned out to be as important as OA. The costs incurred by
WEA as well as the effects on quality of life equal or surpass those of OA. So far, our understanding of the nature of WEA as compared with OA is poor and far too meagre for scientifically based
preventive strategies. Future research needs to focus on practically all aspects of WEA.
Introduction
From the preventive point of view, the full relationship between asthma and work
environment exposures is of interest. It is generally recognised that some 15% of
adult-onset asthma is attributable to work [1]. Population-based incidence studies
indicate even higher figures [2, 3]. The high figures include all forms of work-related
asthma, occupational asthma (OA) as well as work-exacerbated asthma (WEA).
They are likely to reflect also the multifactorial nature of asthma, with the work environment as one of several interacting etiological genetic and environmental factors.
During the last, almost four decades, the vast majority of research efforts have
focused on asthma with a latency period, specifically induced by sensitisation following inhalation of an asthmagen at work. The level of understanding achieved
about occurrence and mechanisms of this “classical” OA is rather high and should
be sufficient for preventive measures to be taken [4, 5]. However, the more than 250
identified specific inducers of OA, most of which having a low attack rate, explain
Occupational Asthma, edited by Torben Sigsgaard and Dick Heederik
© 2010 Birkhäuser / Springer Basel
299
Henrik Nordman
why a realistic aim of prevention is currently to attain a substantial reduction of
OA. The nature of OA, its resemblance to the much more prevalent non-OA, and
the comparatively benign prognosis are factors explaining why prevention of OA
has been disappointing. These and other factors influencing the prevention of OA
have been listed by Cullinan and his colleagues [4] (Tab. 1). Fortunately, the vast
majority of OA is caused by only a few major asthmagens, such as animal dander,
flour dusts, diisocyanates and natural latex rubber.
It has been argued that exacerbation of pre-existing asthma, non-OA at work
should be included when considering preventive strategies [6]. During the last
decade it has become increasingly evident that the prevention of WEA will eventually be at least as important as the prevention of classical OA [7–9]. The high prevalence of asthma, especially among children and adolescents, makes the well-being of
this sub-group of sensitive future workers a high priority issue.
The chapter gives emphasis to the primary and secondary prevention of the various types of OA. Some examples of successful preventive strategies are described.
Although acute irritant-induced asthma fulfils the criteria of OA, the condition
is almost exclusively caused by accidental exposure to high concentrations of a
respiratory irritant. Preventive measures are, therefore, technical and hygienic,
including worker education, and are not further dealt with in the chapter. [5]. The
Table 1. Factors influencing the prevention of occupational disease [4]
Influences
Societal
Frequency of the disease
Nature of the disease
Perception of the disease
Individual and societal costs of the disease
Technical
Strength of epidemiological or clinical evidence of cause/effect
Identification of risk factors amenable to manipulation
Availability of efficacious technical or organisational means of reducing
important risk factors
Availability of effective methods of secondary prevention
Business
Frequency of the disease
Impact on consumers
Public reputation
Economic costs of the disease
Efficiency and effectiveness of technical or organisational means of
reducing important risk factors
Effects on competitiveness
Influence of employee or consumer organisations
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Prevention and regulatory aspects of exposure to asthmagens in the workplace
need for preventive strategies for WEA is recognised but, so far, there is a paucity of
scientific data on practically every aspect of the condition. Therefore, prevention of
WEA can only be addressed in a state-of-the-art manner. Tertiary prevention aims
at limiting impairment of OA in workers who are already ill. It is, by and large,
synonymous with “management of cases”, which is the topic of the chapter by S.
Burge in this book [10].
The most important elements of the prevention of OA have been listed in
Table 2.
Primary prevention
Primary prevention aims at the avoidance of exposure to agents causing OA and
at the prevention of any such pathophysiological changes that may increase the
Table 2. Measures to prevent occupational asthma
Primary prevention
Measures of regulatory authorities
- legislation
- setting of occupational exposure limits
- labelling of sensitising substances
- making recommendations on the use of sensitisers
- guidance on safe working practices
- labour inspection activities
Screening of products before introduction into the market
Identification of highly susceptible individuals
- vocational guidance
- pre-employment health examinations
Pre-placement education of workers
Control of exposure
- substitution of harmful agents with less harmful
- automation or enclosure of processes
- modification of process or agent to reduce risk of sensitisation
- improvement of ventilation
- working practices to reduce dust concentrations
Administrative measures to reduce numbers of exposed and time of exposure
Personal protective equipment
Secondary prevention
Medical surveillance of workers
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Henrik Nordman
risk of developing the disease. The main measures for assessing and controlling the
exposure in work environments associated with sensitisers were reviewed by Corn
in 1983 [11].
Although rarely practicable, elimination of a sensitiser from the work environment, or to never introduce it into a process is ideal. However, there are many typical high risk work environments, where elimination is impracticable, e.g. the baking
industry, farming, and laboratory animal handling. In such work environments, the
prevention aims at the reduction of the exposure to a minimum [12, 13]. Sufficient
ventilation, healthy work practices and housekeeping are central measures of exposure control in all work environments. Although seemingly self-evident, these are
often found inadequate and grossly neglected. The extent of ignorance and, at least
partly, negligence was registered in a recent survey of bakeries; few were aware of
the existence of an exposure limit for flour, nor of recommended work practices
in bakeries [14]. Intensive education of workers at risk is a prerequisite for a highlevel awareness of risks at the workplace. Investing in education and training programmes should be in the interest of all parties involved.
Testing of products before they are introduced into the market is commendable.
It is also to some extent being done, although the impact of testing has so far been
modest. Most screening is concerned with skin sensitising potency. For instance,
methods such as local lymph node tests in animals probably do not predict the
respiratory sensitisation potency with any greater reliability. Cytokine fingerprinting
is considered a more promising method of assessing respiratory sensitising properties [4]. Elimination of a sensitiser is desirable, but it has rarely been feasible. The
change of natural rubber latex gloves to non-rubber gloves or to powder-free gloves
with a low allergen content is an example of a successful intervention (see below),
reducing exposure as well as the number of exposed, e.g. users of sensitising gloves.
The attempt to substitute a sensitiser may also fail, due in part to the lack of reliable methods for testing substances before introduction. An example of failure often
quoted, is the substitution of toluene diisocyanate (TDI) with the less volatile methylene diisocyanate (MDI), which, however, turned out to be just another respiratory
sensitiser [4, 5].
There are many ways to achieve a reduction of either exposure or numbers of
exposed. In the prevention of OA, the modification of a process or an agent to reduce
the risk of sensitisation has been successfully applied and documented in the detergent enzyme industry. It was achieved by encapsulating enzymes in powder form and,
at least partly, by isolation of processes [16, 17]. It is also an example reminding us
that prevention programmes cannot be “parachuting operations”; continuous surveillance of the work environment and the workers’ health is needed. In this particular case, over the years new enzymes were introduced into the detergent production
processes with unexpected new outbursts of OA [18, 19]. Complete isolation and
enclosure are effective means of exposure control used, for instance, in the handling
of complex platinum salts and in many processes involving organic acid anhydrides.
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Prevention and regulatory aspects of exposure to asthmagens in the workplace
Control of exposure is also exerted by various administrative decisions. The
numbers of workers exposed and the duration of exposure can be restricted by job
rotation, rest periods, shift or location changes where fewer people are working
with sensitisers or irritant exposures [5].
Role of regulatory authorities
In reviews on prevention of OA, the role of regulatory authorities is rarely addressed.
However, regulatory authorities may have a decisive influence on both the primary
and secondary prevention of OA. Preventive measures of the regulatory authorities
include legislation, collecting information (e.g. by registers), the setting of occupational exposure limits (OELs), and supervision by labour inspection.
Laws and statutes define occupational diseases and the level of diagnostic probability, list compensable diseases and causes of disease and determine modes of
compensation.
All these differ from country to country affecting accordingly comparisons of
national statistics [20]. A liberal legislation including compensation for disability,
loss of income inflicted by occupational diseases, and re-education serve as incentives for workers to come forward with complaints of work-related symptoms.
The Finnish legislation on occupational disease and occupational safety and health
(OSH) may serve as an example. Insurance policies for all employees are mandatory,
voluntary for self-employed. Access to occupational health services is mandatory for
all workplaces. Physicians are obliged to report occupational diseases. The modes
and level of compensation is fairly high. As there is little reason to believe that the
true incidence of OA differs from other industrialised countries, the comparatively
liberal legislation is likely to explain the consistently far higher incidence of reported
cases of OA in Finland than in the UK, Sweden and the USA [20].
By setting OELs, regulatory authorities may influence the prevention of occupational diseases in several ways. Most OELs are set as 8-hour time-weighted averages
(TWA). If critical effects, such as irritation or sensitisation, are expected following
brief exposure to high concentrations, a short-term exposure limit (STEL) can be set.
STELs are normally recommended for a 15-minute reference period. OELs are meant
to protect workers from detrimental health effects of exposure by inhalation over a
working life. Health-based OELs are normally set for substances for which studies
on dose-response relationships show either a threshold, i.e. a no-observed-effect level
(NOEL), or a lowest-observed-effect level (LOEL). For respiratory sensitisers, like
genotoxic and carcinogenic substances, NOELs or LOELs are rarely identified. In
such cases it is assumed that any level of exposure might carry some risk. The recommended OELs for these substances are established pragmatically. Exposure-response
data are used in the setting of these final statutory exposure limits, which include
socio-economic as well as technical considerations of practicability [21, 22].
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The setting of OELs are rarely, if ever, enough for the prevention of OA. However, OELs direct the attention of workers, employers and OSH personnel towards
exposure levels and thereby increase the awareness of risks and safe exposure levels.
They may, ideally, be used in the design of new plants and processes to ensure that
exposures will be safe [22].
As full dose-response curves are rarely available for respiratory sensitisers, the
approach may be to provide decision makers with quantitative risk data at different
exposure levels. The final pragmatic recommendation will include socio-economic
considerations and may vary substantially between countries. Flour dust is a good
example. Although distinct exposure-response relationships between exposure to
flour dust and wheat allergen and sensitisation with nasal and asthma symptoms
exist [23–26], there seems to be no identifiable threshold for these effects [27].
Basically the same data on exposure-response relationships have been used for the
setting of OELs, which, however, display a huge range between the health-based
OEL of 0.5 mg/m3 by the American Conference of Governmental Industrial Hygienists (ACGIH) [28] and a maximum exposure limit (MEL) of 10 mg/m3 set by the
Health and Safety Executive in the UK [29]. In this case, it demonstrates the differences between a health-based assessment and a tripartite compromise. Yet another
approach was adopted by the Dutch Expert Committee on Occupational Standards
[30]. Based on advanced analysis of the studies by Houba and colleagues [25, 26],
the excess risk of sensitisation for workers over a working life of 40 years was calculated. An excess risk of sensitisation of 1% and 10% was calculated at exposure
levels of 0.12 and 1.2 mg/m3, respectively. The excess risk at various levels of exposure will eventually have to be weighted against feasibility issues [30].
In many countries, regulatory authorities have made health surveillance mandatory in all work environments associated with health risks. In a preventive
programme launched by the Ministry of Labour in Ontario to reduce diisocyanateinduced asthma (see below), medical health surveillance was one of several elements [31]. In the evaluation of the programme, it was concluded that the decrease
of asthma claims may have been due to several causes, one of which was medical
surveillance. It was stated that medical surveillance may act in several ways. Apart
from early identification of cases, it may improve worker education and general
awareness of hazardous exposures, intensify the use of personal protection and, in
general, working practices [31].
The formal appointment of safety representatives and industrial safety commissions at workplaces are likely to have a favourable preventive impact. The provision
of training and knowledge of the regulations pertaining to bakeries was assessed in
55 bakeries in the UK following the setting of the statutory MEL of 10 mg/m3 and
a 15-min STEL of 30 mg/m3. The study revealed that only a quarter of the bakeries
were aware of the existence of a MEL or a STEL. A copy of a booklet on guidance
on dust control and health surveillance in bakeries, produced by Health and Safety
in Bakeries Liaison Committee [15], was found only in 28% of bakeries. However,
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Prevention and regulatory aspects of exposure to asthmagens in the workplace
companies with an appointed safety representative were much more likely to be
aware of the exposure limits and of the sensitising properties of flour dust, to have
a written risk-assessment and to have provided some training on flour dust work
[14].
Compensation modes and levels may act as incentives for both workers and
employers, i.e. for workers to come forward with their work-related complaints
without fearing to loose their income, and for employers to continuously pay
attention to safety issues at work. The responsibility of authorities is to ensure
that workers receive a satisfactory income replacement indemnity, indemnity for
possible permanent disability and rehabilitation. The compensation systems vary
between countries, the majority being administered by national or regional agencies
and insurance companies. In most countries OA is compensated as an occupational
disease [32, 33]. In countries were agents eligible for compensation are listed, e.g.
UK and France, the continuous up-dating of lists is essential. It is also important
that workers claims for disease caused by agents outside the list are compensated in
alternative ways, for instance by national health insurance [4].
In most industrialised countries the employer is assumed to cover the costs of an
occupational disease [33]. However, few countries have studied the actual partition
of costs. Recently, the distribution of costs of OA in the UK was reported. The study
revealed that as much as 49% of the total costs are borne by the diseased worker,
47% by tax payers and only 4% by the employer [34]. As the authors pointed out,
on one hand it is understandable if workers under such circumstances hesitate to
have their symptoms investigated. On the other, there is little incentive for employers to invest in improvements to reduce exposures.
Finally, data collecting pertaining to OA is an important source of information
and affords a basis for preventive strategies. Data can be collected as sentinel events
(e.g. USA), occupational disease registers (e.g. Finland) and compensation statistics.
Although all these sources of information are known to grossly underestimate the
true incidence of occupational disease, they generate useful information and may
reveal important trends [5].
Pre-employment screening
Health examinations at the pre-employment stage are customary and also commendable as an instrument to protect the health of workers. Inevitably, applicants may be
found unsuitable for a particular work on health-based grounds. This makes it all
the more important that exclusion criteria are clearly defined and based on scientific
evidence. Reasons for exclusion are comparatively few. Probably the only incontestable reason for exclusion is an applicant with an earlier confirmed OA caused by an
agent to which exposure would occur in the new job. If the causative agent is totally
unrelated to exposures occurring in the new job, there is little scientific justification
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for exclusion [4]. Job applicants suffering from non-OA (“community” asthma)
constitute a challenging category. As can be expected when there is a lack of solid
scientific data for precisely formulated guidelines, the practise varies considerably
and often to the disadvantages of the asthmatics [4, 35]. The assessments need to
take into account the severity of asthma. Although scientifically ungrounded, it may
seem justified not to subject persons with severe or moderately severe asthma to a
risk of developing additional respiratory impairment [4].
Although host factors increase susceptibility to OA, screening for and applying
such factors for pre-employment selection is a questionable issue. One reason is that
screening for susceptible individuals may lead to the selection of workers that are
thought to tolerate a work environment associated with harmful levels of exposures,
whereas the preventive approach should be to make the work environment tolerable
to workers despite such host factors [4, 5]. Another reason is the fact that no single
marker of susceptibility has been identified having a predictive value that would justify its use for pre-employment screening [4]. Atopy undoubtedly increases the risk
of sensitisation to high-molecular-weight allergens. However, the predictive value of
atopy is generally accepted to be too low, even in workplaces associated with a high
risk of IgE-mediated sensitisation, such as laboratory animal handling, to be used
for screening purposes; a substantial number of those excluded from work would
never become sensitised. Apart from a low predictive value, the prevalence of atopy
in some 30–40% of young adults is common in industrialised countries and the
exclusion of such a number of otherwise health individuals cannot be justified for
socio-economic reasons [4, 5]. Although smoking is a risk factor in certain work
environments such as laboratory animal work, and in association with exposure to
platinum salts and some acid anhydrides, in practice, smoking has not been considered useful in pre-employment screening, Still, it is appropriate to inform smokers
of the increased risk of sensitisation they may carry in some work environments due
to their smoking habits [5].
Genetic polymorphism and susceptibility to, especially small-molecular-weight
occupational agents has attracted some research interest. In particular, studies on
the human leucocyte antigen (HLAs) have shown some interesting associations with
OA. The HLA-DQB-0501 has repeatedly been shown to positively correlate with
diisocyanate asthma, whereas HLA-DQB-503 has displayed an inverse correlation.
HLA associations also exist with platinum salts and beryllium. The polymorphic
occurrence of glutathione S-transferase (GSTs) and N-acetyl transferase (NAT)
has been used for similar studies of associations with OA and sensitisation. Both
GSTM1 null and NAT 1 and NAT 2 slow acetylator genotypes correlate with
susceptibility to diisocyanate asthma. However, the predictive values of the so-faridentified polymorphic genes are not even remotely high enough for pre-employment selection purposes. Considering the multifactorial nature of OA, it is not to
be expected that a single polymorphic gene would determine the disease, although
it may well increase individual susceptibility or resistance to disease. Irrespective
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Prevention and regulatory aspects of exposure to asthmagens in the workplace
of demonstrated associations with OA, genetic testing, let alone the application of
individual genetic profiles for screening purposes, remains both ethically and legally
a strongly contentious issue [36].
The widely accepted view is that pre-employment examinations are only meant
to establish a base for periodic health surveillance. Due to low predictive values,
they should not be used for screening of potentially susceptible individuals on such
ground as atopy, smoking, or genetic disposition [4, 5, 37, 38].
Secondary prevention
The term ‘secondary prevention’ implies that primary prevention has, in one way
or another, failed. Thus, the purpose of secondary prevention measures is either to
detect occupational disease as early as possible to improve the prognosis of the disease, or, ideally, to detect predictive markers of disease to prevent the development
of clinical disease. Another objective is to prevent further cases from developing in
the same, or similar work environment. The principal means of secondary prevention is regular medical surveillance of employees. There is sufficient evidence showing that duration of exposure after onset of symptoms, as well as continuance of
exposure after onset of asthma, are important prognostic factors, whereas cessation
of exposure is associated with various degrees of recovery [39–41]. It is, therefore,
generally accepted that we can improve the prognosis of OA by early detection of
the disease and by avoidance of further exposure to the causative agent. A consensus
statement by the American College of Chest Physicians (ACCP) recommends routine surveillance of all workers exposed to agents known to cause OA [42].
The main tool of health surveillance is the questionnaire on respiratory symptoms. Questionnaires are normally administered at regular intervals of 6–12 months
in accordance with latencies of particular sensitisers [43]. Although, the first 2 years
of exposure appears to be the most important period, surveillance mostly continues
indefinitely as sensitisation and the onset of OA may occur at a much later time if
exposure continues [4]. Questionnaires have rarely been validated and their sensitivity and specificity are mostly unknown. Workers’ compliance with regularly administered questionnaires has mostly not been assessed. It has been postulated that the
threshold for admitting to work-related symptoms is lower in large companies with
good possibilities to relocate workers, than in small enterprises [4]. The interest in
answering truthfully is likely to vary considerably with expected consequences of
coming forward with complaints. Fear for loosing the job without trusting the compensation systems for being equitably compensated for possible incurred income
loss and disability are poor incentives for participation.
Objective means of surveillance include occasional workplace spirometry and
measurement of bronchial hyperreactivity. Regularly performed spirometry is not a
sensitive tool to detect OA and probably does not add much to a questionnaire [44].
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Unspecific bronchial hyperresponsiveness is a feature of asthma that develops as a
consequence of sensitisation. As a mean of health surveillance, it does not predict
OA [45]. It is also often absent in cases of OA [37].
A new and simple approach has been tested in the Netherlands [46]. A national
surveillance scheme involving the Dutch government, branch organisations and
unions designed to reduce the exposure to flour dust and related allergens was
assessed in the bakery, mill and baking product manufacturing industry in the Netherlands. The central tool was a diagnostic questionnaire developed using the experience gained in a previous study on laboratory animals, to estimate the probability of
sensitisation to wheat and/or A-amylase allergens. The participating 5546 workers
were divided into three categories of probability of developing sensitisation (low
57.4%, intermediate 24.1%, high 18.5%). In the second phase of the programme,
the intermediate-probability group will be evaluated further by occupational physicians and the high-probability group will be referred to an occupational respiratory
clinic. The low-probability group will be enrolled in the next surveillance cycle. The
preliminary results indicate that the simple two-page questionnaire comprising only
19 questions can capture workers with different risks of sensitisation. The approach
is thought to be applicable in small and medium-size enterprises [46].
The regular testing for specific IgE antibody, as rule by skin testing, with workplace allergens has been useful in some work environments. During work with
complex platinum salts, the positive skin test has a high predictive value for the
development of OA [47]. In the production and use of enzyme, e.g. the detergent
industry, skin testing is common. It may, in combination with questionnaires, guide
decision making. It is also used as a kind of biological monitoring of the successfulness of exposure control [48, 49].
Rhinoconjunctivitis is known to precede the development of symptoms from
the lower respiratory tract. It has been shown to precede development of asthma,
although the predictive value was low [50]. This pertains to high-molecular-weight
allergens, whereas rhinoconjunctivitis is less frequent in exposure to low-molecularweight agents [50, 51]. Although rhinoconjunctivitis is a rather poor predictor of
OA, the condition in itself is an occupational disease that ought to be prevented.
Examples of preventive approaches in specific work environments
There are only a few successful preventive programmes that have been both evaluated and published. The study designs have been rather crude, and control groups
have regularly been lacking. There are a number of reasons for the low number of
published studies, most of which pertain to the nature of OA and the low public
profile of the condition (Tab. 1) [4]. Formal assessment of the successfulness of preventive programmes can be expected only in large industries or in certain branches,
for instances bakeries. Only a handful of agents, such as flour dust, animal epithe-
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Prevention and regulatory aspects of exposure to asthmagens in the workplace
lium and dander cause exposure of great numbers of workers and are, therefore,
good environments for interventions [4].
Enzymes
A classical example of primary prevention by alteration of processes and working practices was carried out in the detergent industry in the early 1970s. Asthma
symptoms were described in a detergent factory in the course of the first year of
employment. The symptomatic workers (primarily respiratory) were sensitised to
protease products [52]. Clusters of enzyme allergy in such plants were shown to be
caused by Bacillus subtilis proteases. This resulted in primary preventions measures
to control the exposure. The enzymes were encapsulated to prevent dusting, enclosure of processes was undertaken and the use of protective respiratory equipment
was introduced. A major reduction of sensitisation and symptoms was consequently
reported [16, 17, 53]. Thus, enzyme allergy abated and cases of enzyme-induced
asthma in the detergent industry were rare during the 1990s [48, 54].
However, despite encapsulation of enzyme preparations, the risk of enzyme
sensitisation and respiratory allergy still exists in the detergent industry. The use
of enzymes has increased and new enzymes such as cellulase, amylase and lipase
have been introduced into the washing powder production. Some 25 years after
the outbreaks described above, an epidemic of asthma was revealed in a detergent
producing plant in the UK with a prevalence of enzyme sensitisation of 26% and
work-related lower-respiratory symptoms in 16% of exposed workers [18]. In a
Finnish detergent plant having no recognised health problem, a survey disclosed
a prevalence of sensitisation among exposed workers of 22%, either to protease,
lipase or cellulase compared with unexposed office workers (0%). When interviewed, all sensitised workers reported work-related respiratory symptoms [19].
These incidences emphasise the continuous need of monitoring of exposure, and
education of workers, combined with secondary preventive measures such as health
surveillance.
The enzyme using industry is aware of the minute amounts (nanogram levels)
of enzyme needed to sensitise and have adopted guidelines as low as 15 ng/m3 for
proteases [48]. Health surveillance schemes have been suggested. They include the
periodic skin testing of workers as a secondary preventive measure [49].
Natural rubber latex
Primary prevention by substitution of an allergen is ideal, although not very often
practicable. The interventions applied to decrease latex allergies, including OA,
serves as a rare example of this strategy. In the late 1980s and 1990s, powdered
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gloves with a high protein content was recognised as the cause of high prevalences of
sensitisation to latex and latex-induced allergies including OA among hospital personnel [55–57]. Interventions at an institution level including replacement of powdered gloves having a high protein content with non-powdered, low-protein gloves
have been reported to be successful, leading to cessation or significant decrease in
sensitisation rate. Moreover, already sensitised and even asthmatic workers have
been able to continue working avoiding the use of latex products [58–60].
In 1996, the Ontario Workplace Safety and Insurance Board recommended the
reduction of aerosols of latex proteins and encouraged hospitals to use powder-free,
low-protein or non-latex gloves. At various points of time, hospitals introduced
latex policies including education and medical surveillance. The latex strategies
were temporally associated with a decline in claims for latex-induced asthma [61].
In Germany, a nationwide interdisciplinary information campaign was carried out
in 1997–1998. The campaign was accompanied by a revision of the technical regulations for dangerous substances, demanding only powder-free, low-allergen latex
gloves to be used in institutions providing health-care services. An insurance company covering 60% of hospitals in Germany made financial resources available for
the information campaign. The preventive programme was evaluated by monitoring
compensation claims before and after the campaign, as well as by assessing changes
in glove-wearing behaviour. A temporal association, with a 2-year delay, was registered between the amount of purchased powdered gloves by acute care hospitals
and the fall in reported cases of OA (Fig. 1). The use of powdered gloves decreased
by 50% and the use of non-powered gloves doubled [58, 62]. After recognising that
latex allergy is caused by the inhalation of latex allergen that, adhered to the starch
powder, becomes airborne, the preventive strategies have proven successful in reducing latex allergy. Unfortunately, the possibility of removal of a sensitising agent or
substitution of it with a non-sensitising is a rare occasion.
Laboratory animal allergy
Due to the nature of some working environments, total avoidance of exposure cannot be achieved.
Typical for such environments are animal laboratory work, farming, veterinary
work, bakeries and mills. Laboratory animal handling is associated with a wellrecognised risk of sensitisation and respiratory allergies. In a prospective study of
a cohort of laboratory animal workers, the incidence of allergic symptoms was as
high as 37% in 1979–1980. In 1982–1983 there was a decrease to 10–12%. The
drop in incidence coincided with the introduction of a site order and code of working practice together with an education programme to increase awareness of the
problem. For instance, the use of personal protective equipment became mandatory [63]. A further follow-up of employees recruited in 1987–1990 revealed that
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Prevention and regulatory aspects of exposure to asthmagens in the workplace
Figure 1.
Reported cases of latex-induced occupational asthma (OA) in relation to purchases of gloves
1992–2001 [58].
the incidence of laboratory animal allergy had remained at the same level of about
10%. The predictive value of atopy and sensitisation to laboratory animal during
this 2-year follow-up was 66% and 87%, respectively [64]. The studies by Botham
and colleagues show that primary preventive measures aiming at the reduction of
exposure do reduce the incidence of animal-induced allergic symptoms, and may
make it possible for already sensitised individuals to continue working with laboratory animals.
Flour dust
Considering the size of the exposed population and the high prevalence of sensitisation, the prevention of baker’s asthma appears highly meaningful. Sensitisation
to flour dust may occur in more than 20% of those exposed, and asthma may be
prevalent in 10% [25]. The exposure levels have remained high in the baking industry in general and, contrary to expectations, levels have been even higher in modern
medium and large size bakeries than in small enterprises [14]. Primary prevention
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is difficult due to several circumstances, e.g. the great number of sensitisers including a number of antigens such as various flours, storage mites, enzymes and other
so-called dough improvers present in the baking industry. The background sensitisation to wheat of 2–4% of the unexposed population makes a total avoidance of
sensitisation impossible. As prevention cannot aim at a total avoidance of exposure,
exposure has to be controlled in other ways.
Setting OELs is a way of directing focus on exposure levels. Despite access
to solid data, most countries have set pragmatic exposure limits far too high for
protection. Regulatory authorities have access to better exposure-response data
on wheat flour and A-amylase than for any other occupational sensitisers [23, 24,
27, 65]. It appears that the risk of asthma in a previously un-sensitised population
starts at about 3 mg/m3 and rhinitis at about 1 mg/m3 [23]. Reviews of the scientific
evidence agree that, although no distinct threshold for symptoms or sensitisation
can be identified, the risk of both end-points below 1 mg/m3 would be small and
symptoms would most likely be mild [30].
From the point of view of sensitisation, frequent peak exposures in the baking
process are recognised as an important problem. The scientific basis for recommending a 15-min STEL is, however, lacking. On the other hand, peaks are related
to some specific tasks such as weighing/sieving, mixing, and cleaning. Exposure
levels can be significantly reduced by ensuring sufficient exhaust ventilation and by
applying good working practices such as the use of dredgers instead of hand throwing and vacuum cleaning instead of brushing. A study on 55 UK bakeries revealed a
poor knowledge of elementary working practices for reducing dust levels; only 27%
of bakeries were aware of the existence of an OEL, the MEL or a STEL. Less than
one third possessed a copy of a booklet on guidance to reduce exposures released
by the Health and Safety in Bakeries Liaison Committee [14, 15].
Secondary prevention measures to reduce morbidity by early detection of OA or
sensitisation are common in the baking industry [4]. They comprise pre-placement
evaluations followed by periodic questionnaires on respiratory symptoms and
frequent periodic spirometry, sometimes combined with skin testing. Preventive
programmes have rarely been evaluated. The rationale for carrying out medical
surveillance has been questioned [44]. The accuracy of such a surveillance programme was tested by Brant and colleagues [66]. They carried out a study on 324
supermarket in-store bakeries using a health surveillance programme focusing on
work-related chest symptoms together with specific IgE either to wheat flour or
fungal A-amylase as a surrogate for OA [66]. The surveillance included three stages
starting with a short questionnaire on respiratory symptoms (stage 1), a further
questionnaire on work-relatedness of symptoms, if any, (stage 2) and, finally an
IgE-analysis of a serum samples (stage 3). To assess the accuracy, a cross-sectional
survey was undertaken in 20 bakeries. The surveillance system resulted in a quarter
of those with symptoms reporting that symptoms were work-related; 61% of those
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Prevention and regulatory aspects of exposure to asthmagens in the workplace
with work-related chest symptoms had specific IgE antibodies to wheat or fungal
A-amylase, which corresponded to 1% of the bakers. However, the cross-sectional
survey arrived at a prevalence of 4%. Thus, the surveillance system underestimated
the presence of disease and the conclusion was that a more efficient method of surveillance in bakeries is needed [66].
Much remains to be done to prevent asthma and other allergies in the baking
industry. The setting of health-based OELs will necessarily include socio-economic
consideration of practicability and will not protect the entire workforce. It is obvious
that a successful reduction of OA in the baking industry needs a closer co-operation
between regulatory authorities, branch organisations, unions and OSH personnel. It
should be in the interest of all parties involved to ensure that recommendations and
guidance reaches the workplaces and are actively implemented.
Diisocyanates
An example showing how regulatory authorities can exert preventive strategies is
afforded by a Canadian legislation initiative for the prevention of diisocyanateinduced asthma. In 1983 the Ontario Ministry of Labour introduced a preventive
programme consisting of two components.
As a primary prevention measure, employers had to ensure that the time-weighted average of diisocyanate exposure did not exceed 0.005 ppm. The second component was a mandatory medical surveillance including pre-employment respiratory
questionnaires and spirometry. The questionnaires were repeated every 6 months
and spirometry at least every second year. Respiratory symptoms and/or changes
in spirometry were followed by an assessment by a physician as to the safety of
continuing work [31].
The programme was retrospectively assessed from workers’ compensation
statistics. Following the introduction of the programme, there was an increase in
annual compensation claims, which reflected a more efficient case finding. Starting
in 1991, the claims decreased, whereas claims of OA of other causes remained at an
earlier level. The time from onset of symptoms to diagnosis decreased from 2.7 to
1.7 years and cases had milder asthma. Companies with claims were more likely to
have exceeded the exposure level of r 0.5 ppb. The conclusion was that one or more
component of the programme had a beneficial effect. There was a comparatively
long time lag before the decrease of claims became discernible (Fig. 2). It is possible
that the programme per se has initiated a series of favourable measures undertaken
by separate companies following the introduction of the mandatory programme.
These may have included technical improvements to reduce exposures, more active
education of workers, supervision of working practices including the use of protective equipment, etc. [31].
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Figure 2.
Accepted workers claims of diisocyanate-induced OA and OA induced by other causes in
Ontario [71].
Work-exacerbated asthma
Non-OA, being an increasingly common disease and getting worse because of the
vast number of various irritant exposures in the workplace, has attracted more
and more attention over the last few years. A definition of WEA was suggested in
1995 by the American College of Chest Physicians (ACCP) as concurrent asthma
worsened by non-toxic irritants or physical stimuli in the workplace. The suggested
medical case definition requires a diagnosis of asthma and an association between
symptoms of asthma and work, provided that the subject has had symptoms or
medication before, and experiences an increase of symptoms or needs more medication after entering a new occupational setting [43]. Because of the obvious need
for preventive strategies concerning work-related aggravation of non-OA, Wagner
and Wegman [6] in an editorial suggested that work-aggravated asthma should be
included into the definition of OA. The proposal, although not uniformly accepted
as such by the scientific society [67], led to the now generally adopted, broader
concept of ‘work-related asthma’ covering both OA and WEA [68]. WEA indicates
‘aggravation of pre-existing or coincident adult new-onset asthma because of workplace environmental exposure’ [68, 69].
The need to prevent work-related worsening of any asthma is becoming widely
recognised, but the scientific knowledge about the condition is still scanty. From the
point of view of prevention, it is interesting to note that WEA is associated with a
similar impact on work productivity and loss of income as OA. Some studies indi-
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Prevention and regulatory aspects of exposure to asthmagens in the workplace
cate that WEA may be associated with higher rates of symptoms and exacerbations
than asthma unrelated to work exposures [9].
Preventive strategies including guidelines as to the health surveillance of WEA
require that the condition can be separated from OA. However, the differentiation
between WEA and OA is still a diagnostic challenge and not always possible. Negative specific inhalation challenge tests, when available, often exclude OA. In cases
where inhalation challenges are not practicable, serial peak-flow (PEF) recordings
are normally used; however, they do not necessarily discriminate between WEA and
OA [70].
Regrettably little is so far known about the frequency of WEA and, especially,
what aggravation of symptoms means in terms of health. In the few reports available, the frequency of WEA varies depending on differences in information collection and definition. Focusing on studies including employed adults with asthma,
the prevalence estimates have been in the range of 8–25% [71, 72]. A prevalence
as high as 52% has been reported [8]. The frequency of symptom aggravation was
included in an interview study with 969 asthmatics, where 21% reported workrelated aggravation for symptoms at least once a week [73]. These studies comprise
self-reported symptoms. Objectively assessed work-related functional changes, e.g.
by serial PEF recordings or the monitoring of inflammatory responses, are necessary to assess the health risk involved. Similarly, studies with optimal medication
are needed to evaluate how the increased frequency and aggravation of symptoms
should be managed without risking permanent health implications, but also to
avoid unnecessary discrimination of workers with asthma or bronchial hyperreactivity.
Asthma symptoms may be aggravated by a number of factors such as irritant
agents, dusts, fumes, physical exercise, changes in temperature and strong odours.
When such exposures occur in the workplace, the prevention of choice is to reduce
exposures. However, it is rarely known to what extent the exposure ought to be
reduced to protect asthmatics from aggravation of symptoms. For most substances
exposure-response data are lacking. Solid data on nitrogen dioxide (NO2), a typical respiratory irritant, show that asthmatics and hyperreactive individuals are far
more sensitive to the irritant effects of NO2 than healthy individuals [74]. Safe
exposure levels for asthmatics appear to be as low as 0.2–0.4 ppm, which may
make asthmatics unsuitable for tunnelling and under-ground mining work, where
such low exposure limits may be impracticable. A risk assessment on similar doseresponse data for another irritant, sulphur dioxide (SO2), likewise found a higher
vulnerability of asthmatics to SO2 at or even below current OELs [75]. However,
the assumption that asthmatics are invariably more sensitive to all irritants may
lead to discrimination of asthmatics, similarly to the ungrounded weeding out of
atopics in the 1980s. Exposure-response data are needed for preventive strategies.
A more active use of exposure assessments have been suggested as a routine means
of prevention [76].
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The implementation of scientific-based preventive strategies requires more information on all aspects of WEA. There is a need for clinical assessments of WEA
to obtain objective data, in addition to the self-reported data, on inflammatory
responses and on the effect of continuing exposure on the underlying condition with
or without treatment. It is also important to have exposure assessments to better
understand what levels of exposures are hazardous to asthmatics. Such data are
needed for the production of guidelines to primary health care, and occupational
health personnel. The awareness of WEA should be improved among physicians
working in respiratory clinics.
Asthma attributable to work
A significant proportion of asthma is attributable to work. In a review of available
literature, the authors arrived at a median of 9% for the attributable risk, whereas
inclusion of the 12 studies of the highest quality resulted in a median of 15% [1].
Similar estimates have subsequently been reported in a study on physician-diagnosed asthma in Beijing residents [77] and are even higher for asthma including
wheezing [78].
Only a few population-based incidence studies have been conducted. In one such
study a cohort of 79 204 health maintenance organisation members was followed
for 3 months registering new-onset asthma, re-activation of previous asthma and
exacerbation of asthma. Criteria for onset of asthma attributable to work exposures
were met by 21% [2]. In another large study covering the entire employed Finnish
population aged 25–59 years, the cohort was followed from 1986 to 1998. Combining a register on asthmatics entitled to reimbursement of medication costs and
the census data of 1985, 1990 and 1995 classified according to occupation, relative
risks of the 49 575 incident cases of asthma were estimated. The attributable fraction of occupation for men was 29% and for women 17% [3].
From the preventive point of view, it is interesting that studies, despite different designs, report increased risks of asthma in work environments associated with
irritant chemical agents and dusts [2, 3, 77–80]. An increased risk of OA among
cleaners has been reported repeatedly [79, 81, 82]. In a study on identical twins
discordant for asthma, solvent were found to significantly increase the risk of contracting asthma [83]. Similar exposures may explain an increased risk among shoemakers [79]. Moulds in water-damaged buildings have been suggested as a possible
explanation for an increased risk of asthma among educators [84]. This receives
some support by a meta-analysis on the associations between water-damaged buildings and respiratory outcomes [85].
Population-based studies on attributable risk consistently show risks that are
several times higher than can be estimated from reporting programmes, surveillance
schemes and disease registers [5]. The risk of asthma is frequently associated with
316
Prevention and regulatory aspects of exposure to asthmagens in the workplace
exposures not previously recognised as being sensitising. Several possibilities are
conceivable. To some extent the differences may reflect a failure in finding, or at
least reporting, cases of OA. This is supported by the subsequent analysis by Karjalainen and co-workers [79] of their population cohort. When all registered cases
of OA were deleted from the analysis, an increased relative risk of asthma remained
in the typical high-risk occupations baking 2.13 (95% CI 1.74–2.83) and farming
1.76 (95% CI 1.64–1.89). Both environments are known to cause IgE-mediated OA
without posing diagnostic difficulties.
However, the excess risk of asthma in workers exposed to dusts, gas, and chemical fumes, i.e. irritants, may be due to other reasons. For one thing, diagnostics of
OA has focused on specific sensitisers previously recognised as inducers of OA.
Other unknown and less frequent inducers may have been overlooked. A probably more important explanation is the complex aetiology of asthma. Various host
factors are likely to interact with environmental exposures including occupational
sensitisers, irritant chemicals, dusts, viruses and other microbes. The occupational
exposures are not necessarily the main inducers of disease. However, the attributable factor by definition signifies the fraction of disease in the population that
would not have occurred if exposure to the risk factor had not taken place. Thus,
learning more about the associations between asthma and the work environment
will eventually afford strategies for the prevention of the induction of adult-onset
asthma [5, 6, 61].
Is prevention feasible and worthwhile?
Feasibility issues
OA should to a large extent be preventable. What makes prevention difficult are
the manifold causative agents and the low attack rate in single workplaces together
with a comparatively low public profile [4] (Tab. 1). An evidence-based assessment
of preventive measures concluded that a reduction of exposure leads to a decrease
in the number of workers who become sensitised and who develop asthma [37].
Health surveillance is generally considered an effective way of detecting OA at an
early stage and the prognosis of disease is better in workers who have participated
in health surveillance programmes [4, 5, 37]. Still, few studies have evaluated the
efficacy in terms of reduced morbidity [4, 37].
Some preventive programmes conducted in specific working environments have
included evaluations of the impact. The preventive programmes on natural rubber
latex [58, 59], diiscoyanates [31] and flour dust [46] represent strategies in which
authorities, the industry and unions have joined forces. The programme directed
against diisocyanate exposure was successful in reducing the number of claims,
although the design of the programme did not allow the assessment of the effec-
317
Henrik Nordman
tiveness of separate components of the programme [31]. The successful preventive
programmes on natural rubber latex [31, 58, 59] also represent before and after
comparisons.
The prevention of WEA is a fairly new domain. The knowledge about associations between adult-onset asthma and occupational exposures are still too fragmented for science-based preventive initiatives. Asthma-outcomes have mostly been
based on self-reported symptoms without objective assessments of functional disturbances as a consequence of exposures, and exposure-response relationships have not
been studied. Thus, strategies for prevention of work exacerbation of asthma are
confined to vocational guidance and education of OSH personnel as to health surveillance of asthmatics in work environments associated with dusts and irritants.
Is prevention worthwhile?
Many countries report OA as the most common cause of occupational respiratory occupational disease [20]. Ethically, occupational disease is unacceptable, and
all reasonable means available should be used to prevent it. However, only a few
attempts have been made to assess the costs of OA and possible saved costs as a
result of successful interventions. In one recent study commissioned by the Health
and Safety Executive in the United Kingdom, the true costs of OA were calculated
[34]. The total lifetime costs were derived from both direct costs (e.g. use of health
care resources, treat and rehabilitation costs), and indirect costs (e.g. costs from
sickness absence, labour turnover, compensation and insurance). OA caused on an
average 3.5–4.5 days of absence from work per year. The total lifetime cost incurred
by reported new cases (631 cases) of OA in 2003 was estimated at £ 36–78 millions.
Taking into account that OA is probably under-reported by up to one third, the
costs increase substantially [34].
The cost effectiveness of specific preventive programmes has rarely been calculated. In the successful German preventive programme directed against natural rubber latex (see above), the number of claims decreased drastically with a time lag of
a few years, the use of latex gloves was halved and that of latex-free gloves doubled.
The saved costs of professional training were calculated to exceed those invested by
some ten times [62].
Recent assessments of the socio-economic implications of WEA have arrived at
the conclusion that WEA inflicts considerable costs to employers and the community. Assuming that 15% of asthma can be attributed to work exposures, the annual
costs of WEA in the United states could be as high as US$ 1.6 billion [9]. WEA may
be associated with higher rates of symptoms and exacerbations as asthma unrelated
to work. The effect of WEA on the work productivity and earning capacity is similar
to those of specifically induced OA [9]. It is obvious that more attention has to be
paid to the prevention of WEA in the coming years.
318
Prevention and regulatory aspects of exposure to asthmagens in the workplace
Future developments
A shift in priorities of research related to the complex associations between asthma
and the work environment is discernible. With respect to “classical” OA with a
latency period, the level of understanding of causation of OA is already sufficient
for the implementation of preventive strategies. Preventive programmes should
focus primarily on exposure control and worker education. In the design of such
programmes, there is a need for a more scientific approach; for instance, the
design should include measurable parameters allowing a quantitative evaluation
of programmes. It is important that evaluations of interventions, also smaller ones
conducted in single enterprises and institutions, are reported. Also secondary preventive measures need to be refined. Considering the present extensive routine use
of secondary preventive measures, it should be easy to plan, evaluate and report the
impact of such activities. Further research on markers predictive of OA seems necessary for secondary preventive purposes as well as for the discrimination between
OA and WEA.
WEA has become increasingly important. Epidemiological studies indicate that
WEA is a common problem. It seems to have a similar socio-economic impact as
OA. When allocating resources, it seems advisable to invest in the research of WEA.
The current level of knowledge and understanding of WEA is modest. Although
work-related aggravation of asthma is encountered by occupational physicians at
least as often as OA, the exposures, mechanisms, extent and consequences in term
of the worker’s health are largely unknown. From a preventive point of view, WEA
will be an important issue owing to the still increasing prevalence of asthma and
asthma-like conditions among children and adolescents. There is a need for sciencebased information already at the stage of vocational guidance.
Recognising that some 10–30% of adult-onset asthma is attributable to work,
there is a need for a more profound understanding of the full phenotype of asthma
and, especially, the associations with different work environments. Well-conducted
epidemiological studies frequently show an increased risk of asthma in work environments and occupations not formerly known to be associated with specific inducers of OA. In particular, long-term exposure to a broad range of irritants seems to be
important. A full understanding of the role of work exposures in the development
of asthma may eventually lead to new preventive insights.
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325
Design, conduct and analysis of surveys on work-related asthma
Kathleen Kreiss1 and Dick Heederik2
1
National Institute for Occupational Safety and Health, Morgantown, WV 26505, USA
Division of Environmental Epidemiology, Institute for Risk Assessment Sciences, University
of Utrecht, Utrecht, The Netherlands
2
Abstract
Surveys on work-related asthma serve public health investigation, research on exposure-response
relations, screening for pre-clinical disease, and demonstrations of effectiveness of interventions.
Hypotheses dictate survey design, which include cross-sectional, case-control, cohort, and intervention studies. Tools for characterizing medical risk factors and outcomes include questionnaires,
spirometry, tests of bronchial hyperreactivity, exhaled indices, induced sputum, immunological
tests, and nasal inflammatory indices. An important component of surveys is exposure assessment
to compare a population to existing literature and other surveys with attention to exposure level,
range, and variability among workers. Allergen exposures are challenging to characterize with
respect to peak exposures and evolving immunochemical measurement methods. Exposure assessment strategies are developing rapidly for analysis of exposure-response relationships, whether
for sensitization to allergens or for respiratory symptoms or diagnoses. Power calculations should
guide decisions about whether to implement surveys. Research needs include surveys of populations with irritant or neutrophilic asthma and populations in damp buildings. The relevance of
dermal exposure to sensitizers requires examination as a risk factor for asthma. New causes of
work-related asthma may be identified by surveying industries with excess asthma in populationbased studies that do not have recognized causes of asthma.
Introduction
Our knowledge of new asthmagens, risk factors, and primary prevention of occupational asthma (OA) depends largely on epidemiological surveys of workforces
and populations. Such surveys complement clinical investigation for diagnoses in
individuals, laboratory investigation for mechanisms, and animal experiments for
assessing biological plausibility. We consider surveys as a research tool when sentinel cases in a workforce prompt public health investigation; when primary prevention requires understanding of exposure-response relations or work and worker risk
factors; and when secondary prevention requires attempts to identify pre-clinical
disease. In addition, population surveys can be used in medical surveillance to show
trends and the effectiveness of interventions.
Occupational Asthma, edited by Torben Sigsgaard and Dick Heederik
© 2010 Birkhäuser / Springer Basel
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Kathleen Kreiss and Dick Heederik
These motivations for research surveys dictate the research questions. In the
case of sentinel-event follow-back to workplace populations, the questions may
be whether an excess of respiratory disease consistent with asthma exists and, if
so, whether an occupational cause is apparent. In the case of primary prevention
research, work-related risk factors, such as process and exposures, are examined
for their relations to respiratory health and disease prevalence or incidence. In the
case of secondary prevention studies, worker attributes, such as biomarkers of
immunological responses, are examined for their relations to exposures or clinical
outcomes either in cross-sectional or longitudinal designs. Medical surveillance for
intervention effectiveness is often considered a public health endeavor, rather than
research, since comparison groups are rarely feasible or even ethical. Nonetheless,
intervention outcome can be powerful evidence of causality when changing a particular exposure results in lessening of asthma incidence or prevalence.
In turn, research questions dictate survey design, along with feasibility of
implementation (Tab. 1). Regardless of survey design, it is important to capture
exposure status at the time of disease onset. The simplest and cheapest studies are
commonly cross-sectional surveys of a workforce, but the findings are limited to
associations, which may or may not be causal. To answer the questions of whether
excess asthma is present requires a comparison group. External comparisons might
be another workforce or population-based estimates. In large workforces, internal
comparisons may be possible if the workforce has a range of exposure to implicated processes or agents. If the workforce suspected of having an asthma risk
is large and has many affected workers, case-control studies may be efficient in
determining potential risk factors, but again, only associations are found, and their
interpretation depends on biological plausibility, evaluation of potential confounders, attempts to establish work-related patterns, and replication in other exposed
populations.
To address questions of incidence in relation to occupational risk, longitudinal
cohort studies are advantageous, but are expensive and difficult. Longitudinal studies avoid the temporal confusion of whether environmental conditions precede the
Table 1. Different survey design options and some typical characteristics, assuming appropriate implementation
Design
Cross-sectional
Case-control
Frequency of use
Strength of
scientific evidence
Costs
++++
+
+
++
++
+
Cohort
+
+++
+++
Intervention study
+
++++
++++
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Design, conduct and analysis of surveys on work-related asthma
health outcome. However, employee turnover, particularly with the healthy worker
effect commonly found in populations at risk of OA, may preclude obtaining
follow-up on affected individuals. Similarly, intervention effectiveness studies are
difficult unless subclinical biomarkers of health effect are available, and comparison
populations for longitudinal follow-up are seldom feasible or ethical (unless interventions are being compared).
For some diseases, such as cancer, follow-back of time-space clusters in a workplace is inherently limited by power issues and bias. In contrast, work-related symptoms of asthma as an outcome warrant follow-back much of the time. Although
asthma is a prevalent disease affecting about 10% of the population, adult-onset
asthma has an incidence in the range of 1.2 to 4.0 per thousand person-years [1,
2] based on questionnaire responses. Obtaining incidence density estimates over
employment in a workforce can show whether excess incidence is likely, despite
neglecting workers who may have left because of asthma before a cross-sectional
survey.
Before a study design is chosen
Any survey always starts with a research question, translated into a hypothesis.
The research questions can have a wide range of backgrounds. Employers, workers or occupational health specialists may have questions related to health risks.
These questions may have been initiated by observations from the scientific literature. The question then arises as to whether observations made “in a population
X with exposure to agent Y, with specific health effects Z” are of relevance for
another population with a similar exposure pattern. Research questions may also
be triggered by sentinel cases or a series of cases occurring in a company (place)
or within a narrow time window (time), which require a more thorough survey
to establish whether an excess risk exists and whether determinants in the work
environment may have played a role. An example is the occurrence of OA in
enzyme-exposed workers in the detergent industry in the 1970s. Reports of such
cases to the occupational physician were followed by systematic surveys. Sentinel
case reporting in the U.S. to state health departments have resulted in new asthmagens being established, such as 3-amino-5-mercapto-1, 2, 4-triazole (AMT) in the
pesticide industry [3], and new settings for asthma risk, such as damp buildings
[4, 5].
Research questions refer to what epidemiologists call an occurrence relation. An
occurrence relation describes disease occurrence in relation to known or suspected
determinants. Occurrence relations can be simple and straightforward, as in the
case of a respiratory irritant causing the reactive airways dysfunction syndrome.
Here, symptoms occur immediately after exposure and the relationship manifests
itself easily. In the case of immune-mediated asthma, the natural history is a com-
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plex interplay of exposure and sensitization followed by inflammatory responses.
These relations are modified by individual susceptibility, and the combination of all
relevant variables results in complex time patterns of disease. These elements of the
occurrence relation have to be considered when the research question is translated
into a study design and practical study plan. The study plan contains the design of
the study, what is being measured and how, a power analysis, and a description of
the planned data analysis.
Design options
Cross-sectional studies
Two epidemiological designs usually lead to results relatively rapidly: cross-sectional
surveys and case-control studies. Many cross-sectional surveys on asthma have been
conducted. They consist of measurement of the disease (asthma) prevalence using
questionnaires and sometimes medical tests or other measures of disease presence.
They give a rapid and relatively cost-effective indication of the presence of asthma,
although assessing the work-relatedness of symptoms and signs may require a more
thorough clinical evaluation in the individual worker. Relating excess risk in subgroups to particular exposures, processes, or work indices is another approach to
determining work-relatedness.
The disadvantage of this design is that cross-sectional surveys are extremely
sensitive to the healthy worker effect. A survey by Peretz et al. [6] among bakers
and workers from related industries with exposure to flour and A-amylase showed
that strong differences existed in the prevalence of atopy (against common allergens)
and atopic responses to work-environment allergens. Workers from flour milling
industries were less often atopic than bakers. It is most likely that these differences
are to some extent associated with differences in health-related selection in and out
of the workforce. This type of selection out of the workforce may be associated
with flattening of exposure-response relationships between exposure to allergens
and sensitization, symptoms, and medication use [6, 7], although development of
tolerance may play a role. Few studies exist that have explicitly studied selection
out of the workforce for OA, but a range of studies indicate that health selection
has taken place. It is expected to operate strongly in the case of immune-mediated
OA because affected workers often observe a direct relationship between exposure
and their symptoms. Although there is little doubt that this phenomenon plays a
crucial role in creating healthier current workforces for cross-sectional studies, its
magnitude has yet to be established in most situations. The healthy worker effect
leads to biased results from cross-sectional studies. The bias may affect prevalence
estimates, as well as measures of association between asthma, sensitization or other
outcome, and determinants under study.
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Case-control studies
Case-control studies are not as often applied, but they may be used within (nested)
a cross-sectional study, based on prevalent cases, as a cost-effective and efficient
follow-up design. Usually all cases identified in the cross-sectional survey and a
sample of the controls receive a more detailed evaluation. An important role for
case-control studies is in the evaluation of potential health clusters of asthma. Prevalent studies are likely to have cases and controls that do not adequately represent
either group, and this is especially true for the cases, considering the healthy worker
effect. Incident case-control studies can be nested within longitudinal studies.
Cohort and intervention studies
A cohort is a group of persons who are followed or traced over a period of time. The
concept of a cohort comes from the Roman Empire where it was common to follow
the mortality experience of cohorts (the Latin word ‘cohors’ refers to one tenth of
a legion) of soldiers over time to keep track of the fighting potential of the army.
Cohort studies have been shown to be extremely powerful in OA research.
A simple measure to describe disease occurrence in a cohort is the incidence, the
number of cases with disease divided by the number of individuals at risk at the
beginning of follow-up. This measure of disease is sensitive to loss to follow-up and
competing causes of disease or mortality. A better measure is the incidence rate. An
incidence rate is the number of cases who developed the disease of interest during
follow-up in a cohort of initially disease-free individuals, divided by the accumulated person-time (usually expressed as person-years). Cohort studies require calculation of person-time of follow-up until development of disease or loss to follow-up.
This calculation can be extremely complex when different time-related variables
are involved, such as age, birth cohort, and exposure duration, although most
studies published so far have been relatively straight forward with regard to these
aspects. The Life Table Analysis System software designed by the National Institute
for Occupational Safety and Health (NIOSH), which was developed for mortality
studies, exists to make these calculations. This software can be used for this type of
study as well by manipulating the input structure of the data. An example of a wellconducted study in which this approach was used is the follow-up of laboratory
animal workers by Elliot et al. [8]. A total of 603 workers contributed 2527 personyears over a 12.3-year period. The 12-year incidence rates of laboratory animal
allergy (LAA) symptoms and LAA for all workers were 2.26 (95% CI 1.61–2.91)
and 1.32 (95% CI 0.76–1.87) per 100 person-years, respectively. Higher rate ratios
were seen with increasing reported hours of exposure to tasks that required working
with animal cages or with many animals at one time. The most common symptoms
were related to rhinitis rather than to asthma. If incidence rates are available for an
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exposed and a control group, incidence rate ratios or relative risks can be calculated
as a measure of association between exposure and disease.
Several approaches have been used in the design of cohort studies for OA. Most
published cohort studies have been of workforces in one company, one industry, or
one job category. Cohort studies among individuals naïve towards their occupational
exposure, often among apprentices, have given good insight into the determinants of
OA and allergy [9]. Apprentices become exposed to specific agents for the first time
in their lives because some occupational exposures may be exceptionally rare in the
general environment. This is true for spray painters exposed to isocyanate monomers and oligomers. Domestic or general environmental exposure to these agents is
usually absent. Alternatively, some allergens are not exclusively found in the work
environment, but exposure in the work environment is orders of magnitude higher
than in other environments. This is likely the case for allergens like latex and wheat
allergens. Studies of apprentices are extremely powerful, but studies among workers, starting with a cross-sectional survey and following disease-free workers with
only a brief exposure history, have comparable potential as demonstrated in studies
of the baking industry [10]. Cohort studies for non-allergic asthma in relation to
irritant or bioaerosol exposures are in their infancy.
Cohort studies for asthma usually involve an extensive baseline survey and
regular follow-up surveys. The incidence rate of development of sensitization is
relatively high – between 1 and 10 cases per 100 person years of follow-up – and
cases may occur within the first few months of exposure [11–13]. The frequency of
follow-up surveys varies in available studies. A reasonable follow-up frequency is
one survey per year, although studies of mechanistic aspects of development of sensitization may require more intensive follow-up [14]. Unfortunately, follow-up time
in most studies has been relatively short, not more than a few years. Studies with
more than 5 years of follow-up [12, 15] show that asthma or sensitization incidence
remains high after the first few years of follow-up. This finding is at odds with the
suggestion that risk declines rapidly after the first month of exposure. Because most
studies have been relatively short, little is known about the predictive value of determinants of asthma and allergy over longer periods of time. Most published cohort
studies are prospective, but retrospective studies exist [15]. Retrospective studies
make use of information collected earlier, and in the example of Kruize et al. [15],
pre-employment testing information was available for a population of laboratory
animal workers.
Some cohort studies have not focused on incidence, but considered change in a
physiological parameter like lung function over time. Few such studies have been
conducted among populations with a high risk for developing OA. The study by
Portengen et al. [16] showed that the decline in lung function over a 3-year followup period was strongest among sensitized and allergen-exposed individuals compared to non-exposed or non-sensitized individuals. This type of cohort study is
often referred to as a longitudinal or repeated measurement study.
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Health outcome tools
Questionnaires
Standard questions about respiratory symptoms and physician diagnoses should be
selected from validated instruments, with a view to the purpose of the survey [17,
18]. If the aim is to identify possible cases, then questions of high sensitivity are
needed. In an analytical epidemiological study of risk factors, questions with high
specificity for asthma should be used. In emerging issues, such as asthma among
occupants of damp buildings, analytical comparisons can be made with other populations if identical questions are used.
For asthma, the long-standing American Thoracic Society-Division of Lung Disease (ATS/DLD) questions [19], designed for study of chronic bronchitis and emphysema, have largely been replaced with questions used in the European Community
Respiratory Health Study (ECRHS), which were derived from the International Union
Against Tuberculosis and Lung Disease questionnaire [20]. A combination of symptoms or weighted score can predict airways hyperreactivity, clinical diagnosis by an
expert panel, incident asthma, and other asthma outcomes in relation to risk factors
for asthma [21–24]. Regardless of questions, symptoms-based definitions of asthma
result in classifying a much higher proportion of a worker population as having
asthma compared to the self-report of physician-diagnosed asthma. Questions aimed
at establishing associations between symptom patterns and work-related exposures
are an important issue in questionnaires focused on OA. Work-related symptom patterns include predominance at work, exacerbation during spills, or a delayed immunological response after working hours or during the night. Similarly, symptoms may
progress over the work week or improve during holidays or weekends.
In the United States, questions from the Third National Health and Nutrition
Examination Survey [25], the National Health Interview Survey [26], or the Behavioral Risk Factor Surveillance Survey [27] allow external comparisons regarding
symptom and diagnosed asthma prevalences in a working population in comparison
to national or state-based prevalences. In Europe, comparisons of symptom and
diagnosis prevalences in workforces can be compared with ECRHS prevalences.
Such comparisons can establish that excesses of asthma or chest symptoms exist in
working populations suspected of occupational lung disease [5, 28, 29].
Cross-sectional questionnaire analyses can also address asthma incidence in
relation to employment or process changes during employment. The ATS/DLD and
ECRHS questionnaires ask persons with physician-diagnosed asthma for their age at
asthma onset. This information, in conjunction with employment date and current
age, allows calculation of incidence density of asthma in adulthood prior to employment, in comparison with incidence after onset of employment, both expressed
as asthma diagnoses per person-months at risk. With this rate ratio comparison,
employment-related incidence excesses as high as 7.5-fold have been documented in
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damp buildings with high prevalences of building-related chest symptoms [5, 30].
The healthy worker effect tends to underestimate asthma incidence after employment
in cross-sectional studies, so such rate ratio comparisons may be lower than would
be found in a longitudinal cohort study.
All strong questionnaires need a work history module, which is usually tailored to
the workforce being studied. As mentioned above, dates of employment or entry into
job titles with exposure correlates can be used to calculate incidence density of asthma
before and after exposure began. Work history can be linked to exposure assessment to
calculate cumulative, average, or peak exposure based on job-exposure matrices. In the
absence of extensive quantitative exposure assessment, questionnaire indices of exposure, such as process, job title, tasks, history of spill exposure and frequency, duration
of exposure, and use of respiratory protection can be associated with respiratory health
outcomes. Some exposure risks, such as spills, may never be characterized quantitatively
because they are unanticipated and unmeasured events. Nonetheless, these qualitative
risks may have considerable public health value in suggesting priorities for intervention
and the possible importance of peak exposures. Examples include early studies of the
pulp and paper industry, which has a risk of reactive airways dysfunction syndrome
[31], and the isocyanate industry, in which spills were associated with asthma cases [32,
33]. In early studies within an industry, such qualitative associations may help prioritize
needs for careful exposure assessment, such as in process-related risk.
An evolving area of possible exposure risk that can be partially addressed by
questionnaire is dermal exposure to allergens and sensitizers. In a new waferboard
factory, incident asthma-like symptoms were associated with affirmative responses
to questions about skin and clothing stains from isocyanates [34]. Dermal exposure
assessment is in its infancy, with attempts to estimate relative exposures with skin
wipes, surface wipes, cotton glove burden of analytes [35], and adhesive tape stripping [36]. In the meantime, questions reflecting the likelihood of skin integrity, use of
skin protection, stains where applicable, and dermatitis may push this field forward
in relation to asthma prevention measures [37]. For another sensitizing occupational
lung disease, beryllium disease, skin exposure may be an important route of sensitization [38]. The parallels with latex asthma, in which latex dermatitis may be a sensitizing event, are intriguing. Considerable animal evidence exists for sensitization via the
dermal route for latex, beryllium, and isocyanates [39–41].
Socioeconomic implications of OA can be addressed by adding questionnaire modules pertinent to absenteeism due to respiratory disease and quality of life. Examples
include SF12 and the Marks’ asthma quality of life questionnaires [42, 43].
Spirometry
Although asthma attacks precipitate airways obstruction, the utility of spirometry in
surveys of populations at risk of OA is limited. Between asthma attacks, asthmatics
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usually have normal spirometry. Hence, cross-sectional studies of spirometry at work
are seldom sensitive in identifying those with physician-diagnosed asthma or workrelated asthma. In workforces at risk for asthma, bronchodilator testing of those with
abnormal spirometry of an obstructive nature may differentiate asthmatic workers
from those with chronic obstructive lung disease. Cross-shift and cross-week changes
of spirometry are labor-intensive and also insensitive. Thus, the serial peak flow or
serial spirometry that is of clinical value in documenting work-related decrements
over several weeks of measurements [44] is seldom practical in a survey setting [45].
Compliance with several measurements per day on work days and days away from
work is rarely obtained on a population basis, even when restricted to those with
symptoms, measured bronchial hyperreactivity, or physician-diagnosed asthma.
Long-standing asthma can result in partial irreversible airflow limitation. For
longitudinal cohort studies, assessment of average decrements of forced expiratory
volume in one second (FEV1) over periods of time may be of some utility, although
such evaluation is more pertinent to chronic obstructive lung disease than asthma.
In such studies, the detection of excess declines in FEV1 in individuals over an
interval is dependent on frequency of measurement, spirometry quality, and time of
follow-up [46]. Recent NIOSH software for evaluation of longitudinal spirometry
makes these analyses much easier [47].
Bronchial hyperreactivity
Methacholine or histamine challenge tests are done in field settings with abbreviated
protocols. In those with chest symptoms suggestive of asthma, documented hyperreactivity is an attractive objective measure of asthma. However, in workforce populations, normal tests are frequently found in those reporting physician-diagnosed
asthma. This insensitivity may reflect adequately treated asthma. One approach
to objective documentation is to aggregate those with prescription asthma medication with those with documented hyperreactivity and those with bronchodilator
responses on spirometry (an alternative test for reversible airways obstruction in
those with abnormal spirometry) [5].
Exhaled indices
Exhaled nitric oxide (eNO) has been adopted in clinical settings as a means of
monitoring control of allergic asthma. As a marker of eosinophilic inflammation,
increased eNO may indicate inadequate medication or compliance. Recently, eNO
has been used in general population field studies in the evaluation of asthma [48].
However, the applicability of this test among workers at risk of immunological
or irritant OA in surveys of current workers has not been established [49, 50].
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Some investigators have examined eNO as a marker of inflammation in relation
to workplace irritant or particulate exposures, sometimes excluding known asthmatics [51, 52]. Inconsistent findings have been found for irritant and particulate
exposures [53, 54] and also for biomass exposures [55, 56]. A cross-sectional
study among farmers demonstrated that eNO levels were positively associated with
endotoxin exposure in non-smokers and non-atopics [55]. However, in buildingrelated asthma associated with biomass markers, eNO was not higher in those with
either physician-diagnosed asthma or epidemiologically defined asthma based on
symptoms [56]; however, the pathophysiology of dampness-associated asthma may
not involve immunoglobulin E (IgE) and eosinophilic inflammation [5], which are
associated with elevated eNO.
Exhaled breath condensate is currently being investigated in field studies as a
means of identifying malondialdehyde as a biomarker of oxidative stress, inflammatory markers such as cytokines, and to establish dose for metals and solvents [57].
In a building-related asthma study, interleukin-8 in exhaled breath condensate was
higher in those with physician-diagnosed asthma and with work-related respiratory
symptoms compared to controls [56].
Induced sputum indices
Sputum induction for cell differential counts has been investigated in clinical settings evaluating those with OA [49]. Those with IgE-associated asthma usually have
increased sputum eosinophilia with exposure. Some evidence exists for sputum neutrophilia in those with isocyanate asthma, irritant exposure as in paper mill workers
[58], and microorganism exposure. Induced sputum has also been used for evaluating other inflammatory markers, such as interleukins, matrix metalloprotease-9
activity, and activated basophils by flow cytometry. Induced sputum is difficult for
survey participants in field settings, particularly in those without symptoms [59].
Accordingly, survey application has been limited. An investigation of mushroom
workers used spontaneous sputum induction in those with cough and no other
diagnoses, rather than induced sputum in the entire population [60]. Others have
induced sputum in clinical settings [61, 62].
Immunological tests
Atopy is a risk factor for asthma caused by high-molecular-weight agents in
the workplace, although its predictive value is not high enough to warrant preplacement screening in the workplace. Exposure level determines the likelihood of
developing asthma due to high-molecular-weight sensitizers because specific sensitization is the primary mechanism. Individual susceptibility, such as atopy, is merely
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Design, conduct and analysis of surveys on work-related asthma
a modifying factor for exposure-response relations, but may merit characterization
of atopic status in exposure-response studies. The means of assessing atopy are by
questionnaire regarding history of hay fever, eczema, and asthma; by total IgE measurement in serum; by antigen-specific IgE levels for a panel of common allergens;
or by skin prick tests to a similar panel of common aeroallergens.
In field surveys of populations at risk for asthma, tests of specific immunological
reactivity are often an outcome variable or an intermediate variable between allergen
exposure and OA. Tests for specific immunological reactivity include specific serum
IgE and IgG antibody tests and skin prick tests to specific allergens. Thus, workplace
surveys exist that examine reactivity to wheat allergen, A-amylase, soy antigens, rat
urinary protein, snow crab antigen, latex antigens, and many others. There is no role
in field studies for specific inhalation challenge to assess immunological reactivity to
an inhaled allergen, since these tests must be performed in specialty clinical centers
and entail risk that is unacceptable outside of a clinical diagnostic context. In other
occupational lung diseases, cell-mediated immunological reactivity is an endpoint
and intermediate outcome in epidemiological study. The dominant example is testing
for beryllium sensitization in beryllium-exposed worker surveillance with the beryllium lymphocyte proliferation test [63]. However, such lymphocyte tests may have
a role in field surveys for low-molecular-weight antigens such as isocyanates [64] if
shown to play a role in pathophysiology of isocyanate asthma [65].
Nasal inflammatory indices
Work-related nasal disease is common and may be a risk factor for OA [66]. Thus,
a variety of tools have been considered for characterizing nasal disease, such as
nasal eNO and nasal lavage for inflammatory markers; nasal swabs for cytology;
nasal inspiratory peak flow, rhinomanometry, and acoustic rhinometry for nasal
resistance; and nasal morphometry. Their application in field studies has been limited because of participant reaction, invasiveness, time, and the need to establish
normal values. Murgia et al. [62] demonstrated higher interleukin-6 in nasal lavage
of chromium-exposed electroplating workers in comparison to controls.
Exposure assessment in occupational asthma surveys
There are several reasons to include an exposure assessment component in OA
surveys. The first and most basic one is for documentation purposes. To allow
meaningful comparisons with the existing literature and between different studies,
it is useful to have some insight into the level, range, and variability of exposure of
workers in a newly conducted survey. Results from a survey are difficult to put in
context, especially when there is no background information about the exposure.
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Information about specific industries or job titles is usually not sufficient because
exposure levels can differ between countries for the same industry and job title.
Also, the level of technological development may differ between companies, resulting in exposure differences. A basic impression of the exposure can be obtained
simply by monitoring a random sample of workers and taking a limited number of
repeated measurements for each worker.
Another reason to monitor exposure is the analysis of exposure-response relationships and to evaluate the effect of interventions. These two aims require more
elaborate exposure assessment strategies. The analysis of exposure-response relationships for high-molecular-weight allergens and asthma has a short history and
started in the early 1990s. Results from this research have shown that a range of
exposure-endpoint relationships exist for OA. These studies have indicated that
lowering exposure will most likely reduce the burden of disease, although a residual
risk can probably not be avoided completely. There is still very little experience
with intervention studies in the field of OA, and the need to improve the methodology and implement exposure studies is clearly present [67]. The most thoroughly
described evidence involves latex gloves. Use of powder-free gloves is known to
be associated with considerably lower exposure to latex allergens [68]. Follow-up
studies in dental school student cohorts have shown that introduction of powderfree gloves is associated with disappearance of latex sensitization and asthma [69].
Some useful references exist that describe some methodological issues for intervention studies in occupational respiratory disease epidemiology. Brosseau et al. [70]
describe the exposure assessment component of a pilot study of the Minnesota
Wood Dust Study. In this study, an intervention was undertaken in 48 businesses
(written recommendations, technical assistance, and worker training). The comparison companies received only written recommendations. Changes from baseline
in dust concentration, dust control methods, and worker behavior were compared
between the groups 1 year later. Workers in intervention relative to comparison
businesses reported greater awareness, increases in stage of readiness, and behavioral changes consistent with dust control. The median dust concentration change in
the intervention group from baseline to follow-up was 10.4% lower than the change
in comparison businesses [71, 72]. Meijster et al. [73] describe results from a fouryear intervention program in the baking and flour processing industry with similarly
modest exposure reductions. These changes in exposure were smaller than expected
and illustrate that conducting effective rigorous interventions is extremely complex.
Such changes can hardly be detected without quantitative exposure measurements.
Occurrence of and variability in allergen exposure
Little information exists about how exposure to allergens in the work environment
occurs. A recent study among bakery workers, who are exposed to allergens in
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Design, conduct and analysis of surveys on work-related asthma
particulate form, has shown that workers are exposed to a high number of peaks
over a work shift (Fig. 1). These peaks are usually associated with a range of different tasks. Between the peaks, exposure is extremely low. There is hardly any background exposure to particulates. More than 75% of the work shift time-weighted
average exposure could be explained by peak exposures during a limited set of
well-defined tasks and activities [74].
For some other high-molecular-weight allergens, like latex and rat urinary allergens in lab animal settings, detailed information is lacking, but it is likely that for
allergens in particulate form, peaks are equally important. Peak patterns of exposure
can easily be explained by the properties of particulates. Earlier studies among bakery workers have shown that most of the particulates are relatively large, > 5 Mm.
Particulates of this size remain airborne for only a short period of time because of
gravity. Sedimentation is rapid and occurs often in less than a minute to maximally
a few minutes. Thus, exposure occurs only when bags are opened, flour is used for
manual dusting of dough, and brooms or pressurized air are used for cleaning.
Figure 1.
Typical peak pattern of dust exposure for a bakery worker with some major tasks during the
peaks described (from the study described by Meijster et al. [74], figure not published in the
original paper, courtesy of the author).
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For low-molecular-weight allergens, which are more often gaseous, constant low
background exposure may theoretically occur, with peaks superimposed, dependent
on the performance of certain tasks. However, the evidence for this is very limited.
Recent studies among car spray painters, who are exposed to isocyanate monomers
and oligomers in gaseous and solid (particulate) phase suggest that the exposure is
often undetectably low, probably because of the presence of rigorous exposure control measures like spray-painting booths and local exhaust ventilation [75, 76]. The
exposure is detectable when high exposure tasks are performed and when tasks are
performed without exposure control measures: during spraying outside the booth,
when spills occur, during preparation of paints, etc. So, also here, exposure occurs
as a series of peaks over time.
Exposure to particulates and gases is always extremely dynamic and varies
strongly over time and space. Pronk et al. [75] describe results from a large measurement series among car and industrial spray painters. For each worker, repeated
measurements were performed (Fig. 2). These results show that car spray painters
Figure 2.
Variability in isocyanate exposure for each sampled worker and by type of industry (car spray
painting and industrial spray painting). Total isocyanate exposure (monomer and different
oligomers) is expressed in Mg/m3 NCO. Closed circles refer to detectable levels, open circles
refer to measurements below the detection limit, which are plotted as 2/3 of the detection
limit (Pronk et al. [75], with permission of the publisher).
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Design, conduct and analysis of surveys on work-related asthma
are exposed to lower concentrations than industrial spray painters, but that the variability within a worker (over time) is large, up to several orders of magnitude. Reliable estimation of exposures for epidemiological study requires a sufficient number
of samples and attention to design options for the exposure component.
Sampling for allergen exposure
Good quantitative epidemiological studies with state of the art exposure assessment are as yet lacking for most allergens. An important explanation is the absence
of methods to measure the exposure accurately for most sensitizers. Exposureresponse modeling for sensitizing agents is also complex. Asthma is a variable
condition, and a sensitized individual reacts to levels to which he or she did not
react before becoming sensitized. This complicates identification of levels that
induce sensitization or that induce asthmatic reactions. However, these issues do
not make exposure-response analyses impossible. For many diseases, differences in
susceptibility exist between individuals, but exposure-response relationships have
been described.
Low-molecular-weight sensitizers are usually gaseous or partially in solid phase
and have to be measured using conventional equipment for gaseous or mixed phase
(solid and gaseous) pollutants in combination with chromatography and, in some
cases, mass spectrometry. High-molecular-weight sensitizers have to be analyzed
with immunochemical techniques to measure the allergen content of the dust.
Currently, dust sampling equipment is based on particle size-selective sampling
using health-based definitions of particular size fractions, such as respirable dust,
thoracic dust, and inhalable dust [77]. Since sensitization and respiratory symptoms
can occur in the upper and lower airways (rhinitis and asthma, respectively) inhalable dust, reflecting the dust particles that can penetrate the respiratory system,
is the dust fraction that is measured most commonly in modern epidemiological
studies. Information on up-to-date equipment can be found in occupational hygiene
textbooks [78, 79].
Other dust sampling approaches have also been used, like the nasal sampler [36,
80–82]. The major application is in situations where conventional sampling equipment cannot be used, for instance, behind face masks [82].
In a very large study among wood workers, passive samplers that hold pieces of
sticky tape were used to capture particulates from different angles. These samplers
can be calibrated against conventional dust sampling equipment. The advantage is
that no expensive sampling pumps have to be used. A disadvantage is that very little
dust is sampled, often not enough for immunochemical analysis. The group that
used these samplers was able to take several thousands of samples over a relatively
short time period and related measured dust exposure with asthma occurrence in
wood workers [83].
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Measuring sensitizers
Immunochemical methods for measurement of high-molecular-weight agents make
use of antibodies, specifically directed against the antigen(s) to be measured. These
antibodies form measurable antigen-antibody complexes, which can be detected
by different labels – isotopes, enzymes, fluorescents or luminescents – in either
inhibition or sandwich assays. Enzyme-linked immunosorbent assays (ELISA)
with chromogenic substrates are most commonly used. Validation studies for each
immunoassay are necessary, and the outcome depends on sensitivity and particularly
specificity of the antibodies used. Specificity of antibodies, as well as the properties
and purity of calibration standards or other reference preparations, can be assessed
by gel electrophoresis and immunoblotting. Sensitivity of inhibition assays depends
mainly on the avidity and concentration of the inhibited antibodies in the assay.
With high-avidity antibodies, a sensitivity of 10–20 ng/ml for protein allergen molecules of 10–20 kDa can be reached. Sandwich assays can be much more sensitive,
depending on the quality of the reagents; if sufficiently specific, the detection system
can be markedly amplified by using various secondary reagents, and in some assays,
sensitivities in the pg/ml range are possible.
Considering the large number of aeroallergens pertinent to asthma, few studies
are available that evaluate the comparability of immunoassays that have been used
to measure them [84–89]. The optimal situation for analyzing allergens immunochemically is reached when the allergen has been identified, and purified allergen
and monoclonal or polyclonal antibodies against the allergen are available.
Low-molecular-weight sensitizers such as platinum salts, isocyanates and other
chemical agents have to be analyzed using standard chemical techniques such as
atomic absorption spectrometry and gas and high-pressure liquid chromatography.
Many low-molecular-chemical sensitizers are highly reactive and this complicates
sampling and analysis.
Exposure assessment strategies
How should the exposure of a population be characterized? Usually several sources
of information have to be combined. Two quantitative exposure assessment strategies exist: measurement for each individual in the population, or measurements for
so-called homogeneous exposure categories, for instance, on the basis of job titles.
Often, exposure assessment on the individual level is considered the gold standard.
However, this strategy is most sensitive to variability of the exposure over time. High
variability over time is known to lead to potentially strong underestimation of the
exposure-response relationship relative to the variability between individuals in the
population. Intuitively, this can easily be understood. When the variability is large
and few measurements per individual are taken, the average exposure for a certain
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Design, conduct and analysis of surveys on work-related asthma
worker will be estimated poorly and can be overestimated or underestimated. This
will occur for each worker, and this misclassification of exposure leads in a regression analysis to underestimation of the exposure-response relationship. This underestimation becomes smaller when more repeated measurements per individual have
been taken. Categorization of the population in homogeneous exposure groups and
use of the measured average exposure per exposure group in an exposure-response
relationship is less sensitive to variability over time. In most cases, this strategy is
known to lead to unbiased relationships between exposure and response. However,
differences within an exposure category are associated with unexplained differences
in health risk. This leads to a reduction of power of this strategy in comparison with
the individual exposure assessment strategy. Despite the lower power, homogenous
exposure groups are the most commonly used strategy. Alternative strategies used in
respiratory epidemiology, which have the same properties as the grouping strategy,
are estimation on the basis of determinants of exposure [90] and strategies, which
consist of combining categorical structures, and individual exposure data [6, 91].
Exposure assessment in epidemiology has developed into a discipline on its own
and covers issues such as categorizing the population into exposure categories, allocation of sampling effort over these categories to obtain accurate estimates of the
average exposure, use of exposure modeling approaches to estimate the exposure,
and evaluation of different exposure assessment strategies as part of an optimization process. These issues have received little attention so far in the field of allergen
exposure, since the emphasis has been on instrumental issues, such as developing
assays and monitoring techniques. However, more and more examples have been
published in which these principles have been applied.
Analysis of exposure-response relationships
In epidemiological studies, exposure-response relationships are usually evaluated
with dichotomous outcomes, even when based on a measurement on a continuous
scale, for example, IgE titer. The most evaluated exposure-response relationships in
allergic respiratory disease are exposure-sensitization and exposure-symptom relationships. However, examples exist in which time to sensitization has been evaluated
[15].
Exposure leads to sensitization, and sensitization in conjunction with further
exposure may lead to an inflammatory airways response that is accompanied by
symptoms, bronchial hyperresponsiveness, airflow variability, etc. For both steps,
risk modifying variables have been identified. Atopic workers have higher risk of
sensitization against high-molecular-weight sensitizers. Smoking and gender might
modify the sensitization risk as well, but the evidence for their roles is weak and
depends on the sensitizing agent. In the case of the low-molecular-weight sensitizer,
platinum salts, smokers are at higher risk, and atopy is not a risk modifier for most
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Kathleen Kreiss and Dick Heederik
low-molecular-weight sensitizers. The consequences of these observations are that
the exposure-response relationship is potentially modified by these factors, and
that the slope of the relationship may differ for different sub-categories of workers.
Recent papers have evaluated these variables in epidemiological analysis of quantitative exposure-response relationships for several high-molecular-weight sensitizers,
such as wheat allergens, fungal A-amylase, and rat urinary proteins [92–96]. In
all cases, the slope of the exposure-response relationship was steeper for atopics
compared to non-atopics. In some cases, there was a suggestion that an elevated
sensitization risk only occurred in non-atopics among the highly exposed, and the
exposure-response relationship was also shifted somewhat to the right.
When one is interested in the relationship between exposure to allergens and
work-related symptoms, all modifiers on the causal pathway between exposure and
symptoms have to be considered. Workers with work-related sensitization are at
higher risk for having or developing symptoms, but atopic workers without workrelated sensitization may also have high symptom rates, as may smokers and older
workers. Despite the fact that Becklake recognized this problem some time ago [97],
most studies have not addressed these modifiers explicitly in their analytical strategies by careful stratification by all potential modifiers.
Power and biological relevance
It is simple to make power calculations in the design phase of a study. Several textbook and internet sites give guidance for specific types of endpoints for a range of
designs (see for instance: http://www.cs.uiowa.edu/~rlenth/Power/). Power calculations help optimize the study design and give insight into what can be expected
from a study of a given size. Power calculations are extremely useful in situations
where major constraints exist in terms of potential number of individuals who can
be included. For instance, study of a disease cluster in a company or section of a
company is usually limited to a fixed number of workers. If low numbers lead to an
extremely low power to detect a biologically relevant increase in disease risk, one
might decide not to study a cluster in greater detail at all, or to use completely different approaches such as risk assessment based on literature reviews and exposure
assessment studies. Studying clusters in a situation where the power to detect an
excess risk is extremely low can be misleading. With large surveys it is possible to
detect small differences in prevalence or incidence between populations or in continuous endpoint variables like lung function or inflammatory markers such as eNO
(Tab. 2). For instance, a survey including several thousand individuals can detect
differences between exposed and non-exposed that are lower than 1%, and such
small changes may defy biological interpretation.
These changes are usually not considered relevant on the level of one individual
and are smaller than the measurement error found on one occasion and the intra-
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Design, conduct and analysis of surveys on work-related asthma
Table 2. Required population size for exposed and controls to be able to detect a difference
in FEV1 between these two populations (2xN) with A = 0.05 and B = 0.20 and a population
standard deviation of 0.5 l (after Berry [100]).
$ (liter/second)
N
0.030
4356
0.060
1089
0.090
484
0.120
272
0.150
174
0.180
121
0.210
89
0.240
68
0.270
54
0.300
44
individual variation in lung function assessed over a period of a few weeks. The
major question does not refer to statistical significance, but to biological relevance
of small changes in respiratory function. Several considerations exist:
-
-
It is known that FEV1 reductions of several hundred milliliters can be associated
with an approximate doubling of the number of individuals with abnormal lung
function when the whole distribution has been shifted [98].
Similarly small lung function reductions are also associated with an elevated
mortality for respiratory diseases and total mortality, underpinning the importance of small changes in lung function on the population level.
What may put this in perspective is to consider the effect of smoking on lung
function. In population studies, usually differences between (ex)-smokers and nonsmokers are between 100 and 300 mL. While such effects are small in the clinical
context, a strong population level determinant like smoking is associated with a
relatively small change in function. This epidemiological paragraph has been extensively discussed by Rose et al. [99]. Lung function is one of the parameters for which
a considerable amount of evidence exists to place small changes in a broader context. For many recent inflammatory markers, such contextual information is usually
not present, making it more difficult to interpret findings from surveys, which are
usually smaller than effects seen in clinical cases.
In large longitudinal population studies, the frequency of follow-up measurements and the time between surveys determine the power to a great extent [100].
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Kathleen Kreiss and Dick Heederik
Very frequent measurement is not useful with long follow-up. Schlesselman [101,
102] has given exact formulas to calculate the population size based on the standard deviations and different combinations of A, B, $, measurement frequency, and
follow-up duration.
Cross-shift studies are a special case of longitudinal studies with an extremely
short follow-up time (8 hours or less). Even when measurements can be performed
with very small analytical errors (< 1–3%), the signal-to-noise ratio of these studies is usually not very good, because the expected changes over the work shift on
the population level may be relatively small and, therefore, difficult to detect. Peak
expiratory flow (PEF) monitoring in OA cases is effective because the changes seen
in PEF may be as large as 30–50%.
Research needs
Although much progress is being made on eosinophilic OA, less survey work exists
for irritant asthma or asthma with neutrophilic inflammation. The recent recognition that the latter phenotypic group may account for half of asthma cases [103] is
particularly pertinent to work-related asthma. Neutrophilic airway inflammation
may be triggered by bacterial endotoxin, particulate air pollution, solvents, cleaners, and ozone. Surveys of agricultural workers and office workers in damp indoor
spaces are now associating bioaerosol exposures, such as endotoxin and fungal
biomass markers, with work-related asthma symptoms [104]. The approaches to
exposure assessment in non-industrial damp spaces differ from that for allergen
exposure, in that settled dust biomass measurements have a role, whereas air sampling has generally not been associated with work-related respiratory symptoms.
In principle, the techniques for surveys examining asthma symptoms in relation to
exposures for low level irritant or biomass exposures should be similar to those for
eosinophilic asthma, with the exception of examining immune health outcomes or
intermediates, such as sensitization. Target industries for such surveys will likely be
motivated by population-based studies that indicate asthma excess that has not been
clinically recognized.
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353
Index
absenteeism
aerosol
breakfast cereals, manufacturer of 267
272
acide anhydride
breath condensate
214
336
British Occupational Health Research
260, 346
agriculture, asthma-like symptoms 164–168
agriculture, exposure in
168–175, see also
Foundation (BOHRF)
bronchial responsiveness
251
233, 241, 335
farm worker
airway hyperresponsiveness
airway inflammation
airway remodeling
allergen exposure
147, 148
7, 8, 148
106, 114, 144
22, 26, 45, 187–199,
allergen exposure, sampling 341
allergen exposure pattern 189, 190
allergic march
car worker
111, 117, 253
209, 216, 218, 224
260–262
chemical sensitizer
chest symptom
chlorine
338–341
allergenic agent
candidate gene
150
239
145
chronic obstructive pulmonary disease
(COPD)
59
cross-sectional study
allergic occupational asthma
111–126
allergic occupational asthma, diagnosis
dermal exposure
detergent industry
diagnosis of OA
118–120
188, 334
284
73, 118–120
5
diesel fume
anaphylaxis to occupational sensitizers 106
diisocyanate
animal allergy
dose-response relation
allergy determinant
33–51
animal allergy, allergen
34, 35
animal allergy, incidence rate 44
antigen-presenting cell
atopy
6, 37, 64, 65, 330
239
257
302, 313–314
283
drug manufacturing plants
dust
125
93, 122, 172–174, 176, 304, 305,
311–313
143
5, 23, 49, 50, 240, 336, 343
dust, flour
122, 304, 305, 311–313
dust, organic
172–174, 176
bakers’ asthma, prediction model 290
bakers’ asthma, prevention
283
employment duration
behavioral risk factor surveillance survey 333
endotoxin
bioaerosol exposure
environmental asthma
346
38
24
5
355
Index
environmental intervention
high-molecular-weight (HMW) agent
8
enzyme, industrial production 122, 123, 302,
HMW prediction model
HMW sensitization
309
European Community Respiratory Health Study
(ECRHS)
host factor
111, 253
290
102, 186
306, 307
human leukocyte antigen (HLA) 50, 51, 210–
333
212, 214–216, 218
exacerbation of asthma 89
exhaled nitric oxide (eNO) 335, 336
Immunoglobulin E (IgE)
exposure,
environmental
in agriculture
to gases
IgE antibodies
207, 223
74, 111, 117
Immunoglobulin G (IgG)
168–175
IgG antibodies
340
to particulates
impairment, asthma related 271
340
incidence of OA
exposure control
income, loss of
282
exposure intensity
282
5
exposure reduction
149
74
exposure assessment 334, 337, 341–343
exposure determinant
36, 142, 149
indoor air quality
93
innate immunity
210
International Study on Asthma and Allergies in
250, 251
exposure standard for allergens 26
exposure-response relationship
19, 20
274
194–199, 343,
Childhood (ISAAC)
101
irritant-induced asthma (IIA) 2, 9, 142, 145,
151, 152, 256
344
exposure-response study
45
irritants
89, 93, 217
isocyanate
farm worker
121, 122, 163, 174, 175, see also
125, 126, 143, 284, 293
isocyanate asthma, prevention 284
agriculture
Fatality Assessment and Control Evaluation
(FACE)
floriculture worker
flour dust
laboratory animal allergy (LAA) 33–51, 121,
264, 284, 310, 311
292
123, 124
122, 304, 305, 311–313
incidence
latency
36
45
prevalence
gases, exposure to
genetic influence
340
7
36
prevention
284
symptoms
36
genetic marker
25
latex, see natural rubber latex
genetic testing
208, 286
lipocalins
genetic test, legal protection 208
genome wide association study (GWAS) 209,
agent
102, 111, 253, 342
agents, measurement of 342
217, 219–221
genotype
34
low-molecular-weight (LMW)
allergen
209
340
chemical
hairdressing chemicals
124
hapten-protein complex
health surveillance, public
152
292, 328
healthy worker effect (HWE) 207, 330
356
3, 4, 141–152
prediction model
sensitizer
lung function
291
186
148, 332
lung function measurement, in mice 148
Index
material safety data sheet (MSDS) 74
PEF measurement
medical surveillance
peak expiratory flow rate 7
286–288
medicolegal management
methacholine
peak flow
10
255, 258
335, 346
persistence, after removal from exposure 7, 8
335
mice, airway inflammation in 148
population-attributable fraction (PAF)
Michigan Occupational Safety and Health
population-attributable risk (PAR) of asthma
Administration (MIOSHA)
292
microbial-associated molecular pattern
(MAMP)
57–67
prediction research
288, 289, 291
prediction-derived diagnostic model 288
169
pre-employment examination
nasal inflammation
pre-employment screening
337
National Health Interview Survey 333
presenteeism
natural history of occupational asthma 101–
prevention of OA
305–308
285
272
8, 26, 282–291, 299–319,
327
107
natural history of work-related asthma 229,
bakers’ asthma
283
cost effectiveness of
230
natural rubber latex (NRL) 263, 282, 283,
NRL allergy, prevention
283
neutrophilic inflammation
346
non-adrenergic, non-cholinergic (NANC) nerve
77
nonspecific bronchial hyperresponsiveness 105
NRL allergy
255
occupational asthma (OA)
specific environment
283
primary prevention
probable OA
prognosis of OA
proteolytic enzyme
PVC
282–286, 301–307, 327
233
71, 72
25
142
258
8, 26, 282–291, 299–319, 327
prognosis of
25
occupational exposure limit (OEL) 303, 304
organic dust
308–313
preventive intervention, isocyanate 293
73, 118–120
prevention
319
286–291, 301, 307, 308, 327
diagnosis
19, 20
284
282–286, 301–307, 327
research priorities
definition
incidence of
284
283
preventive measure
Oasys plotter
284
317, 318
laboratory animal allergy
secondary
73–77
NABR monitoring
305, 318, 319
isocyanate asthma
primary
146
non-allergic bronchial responsiveness
(NABR)
detergent industry
feasibility of
302, 309, 310
system
58
quality of life
274, 275
questionnaire
7, 72, 73, 231, 333, 334
172–174, 176
organic dust, animal study 173, 174
organic dust, human experiment 172, 173
reactive airways dysfunction syndrome (RADS)
2, 9, 107, 142, 145
reactive upper airway dysfunction syndrome
particulates, exposure to 340
peak expiratory flow (PEF) 7, 75–77, 253–262,
346
(RUDS)
146
recovery, complete
red cedar
102
214, 216
357
Index
regulatory authority
303–305
respiratory protective equipment (RPE) 250,
20, 21
International Study on Asthma and Allergies
in Childhood (ISAAC)
285
rhinitis
general population
9, 102, 233, 238
intervention
prospective
second-hand smoke
93
secondary prevention
286–291, 301, 307, 308,
232
workforce-based
sensitization
sensitizer
186, 238, 343, 344
89, 106, 150, 210, 342
sentinel event
327, 329, 292
Sentinel Event Notification System for
Occupational Risks (SENSOR) 292
skin exposure
skin sensitization
skin test
7, 74
smoking
24, 93
331
cross-sectional
intervention
substance P
146
42
survey, epidemiological
327
328, 330
swine barn dust
238
330
331
surveillance scheme
survey design
150
21, 22
study design
case-control
327
101
331
173
Third National Health and Nutrition Survey
specific inhalation challenge (SIC) 77–82,
333
119–121
toluene diisocyanate (TDI) 210–213, 220
atypical patterns of bronchial reactions 81,
transient receptor potential (TRP) channel 152
82
type 1 allergic response 36
laboratory
79
parameter
78
vocational guidance
285
typical patterns of bronchial reactions 80,
work history model, in questionnaire 334
81
workplace
work productivity
80
specific inhalative challenge test 119–121
SPIROLA
300, 301, 314–319
264–268
spirometry
exposure
334, 335
prevalence
sputum eosinophil
77
sputum induction
336
statistical power
cohort
344, 345
6, 37, 64, 65, 330
exposure-response
45
European Community Respiratory Health
Study (ECRHS)
333
4, 5
genome wide association study (GWAS) 209,
217, 219–221
358
96
workforce-based study
21, 22
workplace-related agent
141
natural history
38, 331
frequency
90, 91
work-related asthma (WRA)
331
cross-sectional
93
socioeconomic impact
study,
case-control
272–274
work-exacerbated asthma (WEA) 89–97, 257,
229, 230
89, 112, 229, 230